Three-dimensional structure of chalcone isomerase and methods of use thereof

ABSTRACT

This disclosure provides crystalline flavonoid or flavanone isomerases, isolated non-native isomerase having the structural coordinates of said crystalline isomerase, and nucleic acids encoding such non-native isomerase. Also disclosed are methods of predicting the activity and/or substrate specificity of a putative isomerase, methods of identifying potential isomerase substrates, and methods of identifying potential isomerase inhibitors.

RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 60/229,277, filed Aug. 30, 2000, which is hereby incorporated by reference herein in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This work is supported in part by grant number MCB-9982586 from the National Science Foundation. The Government has certain rights to this invention.

ACKNOWLEDGMENT

This invention was made with United States Government support under Grant No. MCB-9982586, awarded by the National Science Foundation. The Government has certain rights in the invention.

FIELD OF THE INVENTION

The present invention relates to methods for designing mutant chalcone isomerases, and to predicting the activity and/or substrate specificity of native and mutant chalcone isomerases. The present invention further relates to methods for identifying chalcone isomerase substrates and/or inhibitors.

BACKGROUND

Advances in molecular biology have allowed the development of biological agents useful in modulating protein or nucleic acid activity or expression, respectively. Many of these advances are based on identifying the primary sequence of the molecule to be modulated. For example, determining the nucleic acid sequence of DNA or RNA allows the development of antisense or ribozyme molecules. Similarly, identifying the primary sequence allows for the identification of sequences that may be useful in creating monoclonal antibodies. However, often the primary sequence of a protein is insufficient to develop therapeutic or diagnostic molecules due to the secondary, tertiary or quartenary structure of the protein from which the primary sequence is obtained. The process of designing potent and specific inhibitors, activators, or novel proteins has improved with the arrival of techniques for determining the three-dimensional structure of an enzyme or polypeptide whose activity one desires to modulate.

The phenylpropanoid synthetic pathway in plants produces a class of compounds know as anthocyanins, which are used for a variety of applications. Anthocyanins are involved in pigmentation and protection against UV photodamage, synthesis of anti-microbial phytoalexins, and are flavonoid inducers of Rhizobium modulation genes 1-4. As medicinal natural products, the phenylpropanoids exhibit cancer chemopreventive activity, as well as anti-mitotic, estrogenic, anti-malarial, anti-oxidant, and antiasthmatic activities. The benefits of consuming, red wine, which contains significant amounts of 3,4′,5-trihydroxystilbene (resveratrol) and other phenylpropanoids, highlight the dietary importance of these compounds. One strategy for the generation of novel enzymatic activity in flavonoid biosynthesis uses protein-engineering methods and requires a detailed structural knowledge of enzymes within the targeted pathway.

Polyketides are a large class of compounds and include a broad range of antibiotics, immunosuppressants and anticancer agents which together account for sales of over $5 billion per year. Polyketides are molecules which are an extremely rich source of bioactivities, including antibiotics (e.g., tetracyclines and erythromycin), anti-cancer agents (e.g., daunomycin), immunosuppressants (e.g., FK506 and rapamycin), veterinary products (e.g., monensin), and the like. Many polyketides (produced by polyketide synthases) are valuable as therapeutic agents. Polyketide synthases are multifunctional enzymes that catalyze the biosynthesis of a huge variety of carbon chains differing in length and patterns of functionality and cyclization.

Chalcone synthase (CHS), a polyketide synthase, plays an essential role in the biosynthesis of plant phenylpropanoids. CHS supplies 4,2′,4′,6′-tetrahydroxychalcone (chalcone) to downstream enzymes, such as chalcone isomerase (CHI), that synthesize a diverse set of flavonoid phytoalexins and anthocyanin pigments.

An improvement in the understanding of the structure/function of these enzymes would allow for a number of advances in the art, e.g., the exploitation of the synthetic capabilities of known enzymes for production of useful new chemical compounds, for the creation of novel non-native enzymes having new synthetic capabilities etc. A need exists, therefore, for a detailed understanding of the molecular basis of the chemical reactions involved in polyketide, flavanone and flavonoid synthesis. The present invention addresses this and related needs.

SUMMARY OF THE INVENTION

In accordance with the present invention there are presented crystalline chalcone isomerases (CHIs) and the three-dimensional coordinates derived therefrom. Three-dimensional coordinates have been obtained for an active form of chalcone isomerase and the active site thereof, both with and without product or product analog. Accordingly, the three-dimensional coordinates and crystal structure of a CHI provides the ability to develop novel substrates, proteins and enzymatic products of CHI. In addition, the invention provides the use of the three-dimensional structure either alone or together with the structure of polyketide synthases, such as chalcone synthase, to provide a useful template for engineering novel enzymes and enzyme pathways to diversify and modify flavonoid biosynthesis for crop and food sources, as well as providing novel flavanones for intermediates and leads in drug discovery (see WO/01/07579 A2, published Feb. 1, 2001, the disclosure of which is incorporated herein by reference in it entirety).

One aspect of the present invention made possible by the results described herein is a model of the three-dimensional properties of chalcone isomerase proteins. In particular, the invention provides the three-dimensional properties of the active site. The invention features specific coordinates of at least twelve α-carbon atoms defining the active site in three-dimensional space. R-groups attached to said α-carbons are defined such that mutants can be made by changing at least one R-group found in the isomerase active site. Such mutants have unique and useful properties. Thus, in accordance with another embodiment of the invention, there are provided isolated non-native (e.g., mutant) isomerase(s) having at least twelve active site α-carbons having the structural coordinates disclosed herein and one or more R-groups other than those found in native chalcone isomerase(s).

The chalcone isomerase used in the crystallization studies disclosed herein is a chalcone isomerase derived from Medicago sativa (alfalfa) (SEQ ID NO:1). A large number of isomerase proteins from various plant species have primary amino acid sequences showing substantial homology and conservation. Thus, the three-dimensional coordinates disclosed herein can be employed in a variety of methods extending to various isomerase proteins. Accordingly, in another embodiment of the present invention, there are provided methods for predicting the activity and/or substrate specificity of a putative chalcone isomerase from a variety of species. There are further provided methods for identifying potential substrates for a chalcone isomerase, as well as inhibitors thereof.

Other aspects, embodiments, advantages, and features of the present invention will become apparent from the following specification.

BRIEF DESCRIPTION OF FIGURES

FIG. 1A shows the overall reaction catalyzed by CHI, which involves a Michael-type nucleophilic attack of the 2′-hydroxyl on the α,β-unsaturated double bond of chalcone. The numbering systems for chalcones (left) and flavanones (right) are shown.

FIG. 1B is a schematic ribbon diagram of the overall structure of chalcone isomerase (CHI). The N- and C-termini are labeled, as are the β-strands and α-helices of the structure. The position of (2S)-naringenin is also indicated.

FIG. 1C is a stereo-view of the C_(α)-backbone. This orientation is the same as in (FIG. 1A). Every tenth residue is numbered. The position of (2S)-naringenin is also shown.

FIG. 1D is a primary and secondary structure of CHI from Medicago sativa (alfalfa; P28012; see also SEQ ID NO:1, wherein the amino acid at residue 36 is Arg, the amino acid at residue 38 is Leu, the amino acid at residue 48 is Thr, the amino acid at residue 106 is Tyr, the amino acid at residue 109 is Lys, the amino acid at residue 110 is Val, the amino acid at residue 113 is Asn, the amino acid at residue 190 is Thr, and the amino acid at residue 191 is Met) and sequence alignment of CHIs from Phaseolus vulgaris (bean; P14298; SEQ ID NO:2), Pisum sativum (pea; P41089; SEQ ID NO:3), Zea maize (corn; S41579; SEQ ID NO:4), Vitis vinifera (grape; P51117; SEQ ID NO:5), Ipomoea purpurea (morning glory; af028238; SEQ ID NO:6), Petunia hybrida (P11651; SEQ ID NO:7), and Arabidopsis thaliana (P41088; SEQ ID NO:8). α-Helices and β-strands of CHI are indicated above the sequence and the numbering of each protein in parenthesis. Every tenth position in the alignment is dotted. Residues of the (2S)-naringenin binding cleft (underlined), residues of the active site hydrogen bond network (boxed), and other conserved residues (shaded) are indicated as noted. The residues that may influence substrate preference between chalcone and 6′-deoxychalcone are indicated with an asterisk.

FIG. 2 collectively shows 2 (2S)-Naringenin binding and structure of the active site cleft.

FIG. 2A shows a stereo-view of the SIGMAA-weighted |2Fo-Fc| electron density (1.2σ) for (2S)-naringenin.

FIG. 2B shows a stereo-view of residues in the active site cleft. (2S)-Naringenin and a water molecule are also shown. Hydrogen bond interactions are indicated with dotted lines. This view is oriented looking into the cleft. The surface corresponding to Lys 109 and Asn 113 (SEQ ID NO:9) was removed for clarity.

FIG. 2C shows a stereo-view surface representation of active site cleft showing the fit of (2S)-naringenin and a water molecule therein.

FIG. 3 collectively shows the proposed enzyme-mediated stereochemical control of the cyclization reaction. The surface of the binding deft is transparent to show selected residues (grey). The surface associated with Lys 109 and Asn 113 has been removed for clarity. The position of chalcone (hatched) prior to cyclization has been modeled to show the formation of the new bond (dotted line). Hydrogen bond interactions are indicated by dotted lines.

FIG. 3A shows a stereo-view of the proposed chalcone conformation leading to (2S)-naringenin formation.

FIG. 3B shows a stereo-view of the steric clash that prevents (2R)-naringenin formation.

FIG. 4 collectively shows the proposed reaction mechanism of CHI.

FIG. 4A is a view of the active site hydrogen bond network. This view is oriented looking out of the active site cleft. Dotted lines indicate hydrogen bonds.

FIG. 4B is a schematic representation of the active site hydrogen bonds. Distances are indicated in Å.

FIG. 4C is a proposed cyclization reaction catalyzed by CHI. Following nucleophilic attack of the 2′-O— of the substrate on the double bond in a Michael addition, the water molecule stabilized by Tyr 106 (see SEQ ID NO:1) acts as a general acid to stabilize the enolate. This results in formation of a flav-3-en-4-ol intermediate that tautomerizes into the reaction product.

FIG. 5 shows an example of a computer system in block diagram form.

DETAILED DESCRIPTION OF THE INVENTION

In flavonoid biosynthesis, chalcone isomerase (CHI, E.C. 5.5.1.6) catalyzes the cyclization of chalcone (4,2′,4′,6′-tetrahydroxychalcone) and 6′-deoxychalcone (4,2′,4′-trihydroxychalcone) into (2S)-naringenin (5,7,4′-trihydroxyflavanone) and (2S)-5-deoxyflavanone (7,4′-dihydroxyflavanone), respectively. Since chalcone spontaneously cyclizes into (2S/2R)-naringenin, CHI guarantees formation of the biologically active (S)-isomer. (2S)-Naringenin is the precursor of anthocyanin pigments, and mutations in the gene encoding CHI are linked to changes in floral pigmentation. (2S)-Naringenin and other flavonoids also act as small molecule transcription activators that target bacterial transcription regulators governing expression of Rhizobium genes involved in root nodulation.

An “isomerase” or a “chalcone isomerase” includes any one of a family of isomerase enzymes that catalyze the formation of flavonoid or flavanone compounds. Chalcone isomerases are generally monomers.

Mechanistically, CHI catalyzes the cyclization of chalcone with an apparent 100,000:1 preference for the S-isomer over the R-isomer. The second-order rate constant (k_(cat)/K_(m)) for conversion of chalcone by CHI approaches the diffusion-controlled limit with an enzyme-catalyzed rate that exceeds the spontaneous conversion rate by 10⁷-fold. Combined with structural knowledge, the comparison of the spontaneous and enzyme-catalyzed reactions provides insight on how an enzyme accelerates the rate of an intramolecular chemical reaction. The present invention provides a 2.5 Å crystal structure of CHI from Medicago sativa (alfalfa) (SEQ ID NO:1) by multiple isomorphous replacement with anomalous scattering (MIRAS) and the 1.85 Å resolution structure of CHI complexed with (2S)-naringenin by difference Fourier analysis. Atomic resolution structures provide a molecular understanding of how CHI recognizes and catalyzes the stereospecific cyclization of chalcone and provides the ability to modulate natural product specificity and to develop novel isomerase proteins having substrate specificities.

CHI is a functional monomer of approximately 220 residues and has been isolated from a variety of higher plants. (Bednar, R. A. & Hadcock, J. R. J. Biol. Chem. 263:9582-9588, 1988; Dixon, et al. Phytochemistry 27:2801-2808, 1988). The present invention provides the first crystal structure for chalcone isomerase, which resembles an upside-down bouquet that adopts an open-faced β-sandwich fold (FIGS. 1B and 1C). A large β-sheet (β3a-β3f) and a layer of α-helices (α1-α7) comprise the core structure with three short β-strands (β1a, β1b, β2) on the opposite side of the large β-sheet. A search of the Protein Data Bank using DALI (Sander, C. & Schneider, R. Proteins Struct. Funct. Genet. 9:56-68, 1991) revealed no other structurally homologous folds. In addition, a PSI-BLAST search of sequence databases showed that CHI-like sequences are currently found in a number of plants and these sequences display limited homology with other proteins. These results imply that the CHI three-dimensional fold and enzymatic activity are found typically in the plant kingdom. Amino acid sequence comparison of CHIs from a variety of advanced land plants (SEQ ID NOs:1-8) reveals high homology (49% to 82% amino acid sequence identity) with regions of conservation spread uniformly throughout the primary structure (see FIG. 1D). A conservation of residues spanning β3a, β3b, α4, and α6 in the three-dimensional structure among CHIs from different species is demonstrated by the present invention as structural elements of the active site on the protein surface.

The data demonstrates that co-localization of proteins in loosely associated macromolecular complexes is a fundamental component of cellular processes, including flavonoid biosynthesis. CHI and other flavonoid biosynthetic enzymes may associate to provide efficient channeling of substrates and products as shown recently in Arabidopsis thaliana. Although the three short β-strands (β1a, β1b, β2) on the backside of the CHI structure (the relevant portion of the CHI structure is presented in SEQ ID NO:9) form a relatively flat surface that would be ideal for protein-protein interactions, both gel filtration and analytical ultracentrifugation failed to detect association of alfalfa CHI (SEQ ID NO:1) and alfalfa chalcone synthase 2 in vitro.

For the first time the present invention identifies the active site of CHI by identifying the location of (2S)-naringenin in the CHI structure (see SEQ ID NO:9 and FIG. 2). Although a commercially obtained mixture of (2S)- and (2R)-naringenin was used for co-crystallization, only the (2S)-isomer bound the CHI active site. The position of the (2S)-naringenin binding cleft is consistent with inactivation studies that suggested a cysteine residue (Cys 114 in alfalfa CHI, SEQ ID NO:1) is proximal to the active site (Bednar et al. J. Biol. Chem. 264:14272-14276, 1989). In the CHI structure, Cys 114 is near the binding cleft but does not directly contact (2S)-naringenin. The active site cleft is largely apolar and consists of residues from β3a (Arg 36, Gly 37, Leu 38), β3b (Phe 47, Thr 48, Ile 50), α4 (Tyr 106, Lys 109, Val 110, Asn 113), and α6 (Thr 190, Met 191) (FIG. 2B, SEQ ID NO:9). In addition, residues Ala 49, Lys 97, Leu 101, Glu 105, Glu 112, Cys 114, Tyr 152, Val 187, Asp 200 and Leu 201 (see SEQ ID NO:9) contact the ligand (naringenin or deoxyflavanones) or butress the above residues of β3a, β3b, α4, or α6. The apolar methylene carbons of Arg 36 are positioned by a restraining charge-charge interaction from the δ-guanido group to Glu 200 (see SEQ ID NO:9). In addition, the methylene carbons of Lys 109 are fixed by a charge-charge interaction between the side chain amine and Glu 112. Except for Thr 190 and Met 191, the residues contacting (2S)-naringenin are identical among CHIs from different plants (FIG. 1D, SEQ ID NOs:1-8). Although van der Waals contacts dominate the interactions between CHI and (2S)-naringenin, two hydrogen bond interactions exist. The first is mediated by the side chain hydroxyl moiety of Thr 48 bound to the 4′-hydroxyl group of (2S)-naringenin. The second interaction is between a water molecule and the ligand ketone (FIG. 2B). This water molecule and its connected network of hydrogen bonds occupy the same position in the apoenzyme structure. The overall surface topology of the cleft tightly sequesters the (2S)-naringenin molecule (FIG. 2C). The CHI•naringenin complex (SEQ ID NO:9) explains the stereochemical preference of the cyclization reaction; moreover, it suggests why CHIs from different species show moderate selectivity for chalcone and 6′-deoxychalcone as substrates.

“Active Site” refers to a site in an isomerase defined by amino acid residues that interact with substrate and facilitate a biosynthetic reaction that allows one or more products to be produced. An active site is comprised of α-carbon atoms that are indirectly linked via peptide bonds and have the structural coordinates disclosed by the atoms of the residues found in the β3a, β3b, α4 and α6 regions of chalcone isomerase (e.g., Arg 36, Gly 37, Leu 38, Phe 47, Thr 48, Ile 50, Tyr 106, Lys 109, Val 110, Asn 113, Thr 190, and Met 191 of SEQ ID NO:1). In addition, residues Ala 49, Lys 97, Leu 101, Glu 105, Glu 112, Cys 114, Tyr 152, Val 187, Asp 200 and Leu 201 (see SEQ ID NO:1) contact the ligand (naringenin or deoxyflavanones) or butress the above residues of β3a, β3b, α4, or α6. The position in three-dimensional space of an α-carbon at the active site of an isomerase and of R-groups associated therewith can be determined using techniques such as three-dimensional modeling, X-ray crystallography, and/or techniques associated therewith.

Modeling of chalcone, based on the position of (2S)-naringenin, shows that a slight rotation of the trihydroxyl-ring outward in the direction of the active site opening places the 2′-hydroxyl group in position for nucleophilic attack on the α,β-unsaturated double bond of the coumaroyl moiety (FIG. 3A) This rotation preserves the position of the chalcone backbone and the hydrogen bonds between Thr 190 and the water molecule at the backside of the binding site. Formation of (2R)-naringenin would require substantial rearrangements in the active site of CHI due to significant steric clashes between the trihydroxyl-ring and CHI side chains. Although rotation of the trihydroxyl-ring away from the active site entrance could reposition the 2′-hydroxyl group for attack on the opposite face of the α,β-double bond, the side chain of Val 110 sterically prevents this movement from occurring (FIG. 3B). In addition, the opposite side of the substrate double bond could be positioned for attack by the 2′-hydroxyl group in the formation of (2R)-naringenin. This alternative cyclization would be accomplished by rotation of the coumaroyl moiety outward towards the solvent accessible active site entrance. However, Leu 38 and Lys 109 constrain the orientation of the coumaroyl moiety in the binding cleft. Architecturally, the CHI active site limits the substrate's available conformations to ensure stereospecific product formation.

Subtle variations in substrate preference reflected in the K_(m) values for chalcone versus 6′-deoxychalcone exist between CHIs of different species (Dixon et al. Phytochemistry 27:2801-2808, 1988). CHIs from legumes, such as alfalfa, prefer 6′-deoxychalcone as a substrate but the enzymes from non-legumes, like petunia, optimally use chalcone. The structure of the CHI•naringenin complex (SEQ ID NO:9), viewed with reference to the amino acid sequences of different CHIs, show that Thr 190 and Met 191 may partially modulate substrate preference. In the CHIs from non-legumes, a serine and an isoleucine replace Thr 190 and Met 191 (see SEQ ID NO:1), respectively. These two differences may better accommodate the 6′-hydroxyl moiety of chalcone due to a modest increase in active site volume in the vicinity of the trihydroxyl ring.

The present invention provides for the first time the intramolecular reaction of CHI (SEQ ID NOs:1, 9-11) with its product. CHI catalyzes an intramolecular reaction utilizing a substrate-derived nucleophile and a carbon-carbon double bond as a Michael acceptor. Two reaction mechanisms have been proposed for (2S)-naringenin formation by CHI. One involves nucleophilic catalysis by an active site residue that forms a covalent intermediate that is released after a SN₂ displacement by the 2′-O⁻ of chalcone. The other mechanism invokes general acid-base catalysis employing an enol intermediate. The structure of CHI clearly supports the latter mechanism.

Examination of the CHI•naringenin complex structure (SEQ ID NO:9) reveals a hydrogen bond network at the bottom of the binding cleft centered about the water molecule that contacts the ketone of (2S)-naringenin (FIGS. 4A and 4B). Of the five amino acids contributing to this network, only Thr 48 and Tyr 106 are conserved in all CHIs (SEQ ID NOs:1-8). The position of the water molecule between (2S)-naringenin and Tyr 106 (see SEQ ID NOs:1, 9-11) suggests a reaction mechanism in which the tyrosine activates the water, allowing it to serve as a general acid in the cyclization reaction (FIG. 4C). In the proposed reaction mechanism, the 2′-O⁻ (pK_(a)˜7-8) forms in solution as suggested by studies on the spontaneous cyclization of chalcones. The negatively charged oxygen then attacks the carbon-carbon double bond of chalcone utilizing a Michael addition with the water molecule at the backside of the active site acting as the general acid in the transient protonation of the intermediate enolate.

Accordingly, for the first time, the invention provides the ability to modulate activity of the active site of CHI to design novel enzymes to catalyze the synthesis of various flavanones. For example, Tyr 106 (see SEQ ID NO:1) was substituted by phenylalanine and the properties of the mutant CHI (SEQ ID NO:9) compared to the wild-type enzyme. The present invention allows the comparison of the activities of mutants and designed mutants by computer modeling as well as by biological assays. The kinetics for the cyclization of 6′-deoxychalcone by wild-type CHI (SEQ ID NO:1) (k_(cat)=4384 min⁻¹; K_(m)=25.7 μM; k_(cat)/K_(m)=1.71×10⁸ M⁻¹ min⁻¹) versus those of the reaction catalyzed by the CHI Y106F mutant (see SEQ ID NO:1) (k_(cat)=69.0 min⁻¹; K_(m)=29.1 μM; k_(cat)/K_(m)=2.37×10⁶ M⁻¹ min⁻¹) demonstrate that the tyrosine residue contributes to the stabilization of the transition state. The 100-fold reduction in reaction rate is consistent with the decrease in rate associated with the loss of a general acid. However, the observed reaction rate with the mutant remains greater than that of the uncatalyzed cyclization reaction. Thus, the present invention demonstrates that the structural complementarity of the binding cleft to the transition state of the reaction contributes additional levels of catalytic rate enhancement.

A major contribution to rate enhancement in enzymatic reactions results from bringing substrates or reactive centers in the same molecule together in space. As described above, the topology of the binding cleft limits the flexibility of chalcone and eliminates catalytically unproductive orientations by spatially defining an optimal geometry for (2S)-naringenin formation. This effectively channels the ground state conformation of the substrate into a catalytically productive conformation. Together with contributions from general acid-base catalysis, shape complementarity between the CHI binding pocket and chalcone accelerates the cyclization of chalcone 10⁷-fold over the spontaneous reaction rate. Accordingly, the present invention, provides for the first time, the ability to design, model, and assay native CHI and mutant CHI polypeptides.

The three-dimensional structure of CHI (see SEQ ID NOs:1, 9-11), provided herein, together with the structure of chalcone synthase (see WO/01/07579 A2, published Feb. 1, 2001), provides a useful template for engineering experiments that aim to diversify and modify flavonoid biosynthetic pathways for crop and food sources, as well as providing novel flavanones for intermediates and leads in drug discovery.

As used herein, “naturally occurring amino acid” and “naturally occurring R-group” includes L-isomers of the twenty amino acids naturally occurring in proteins. Naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine. Unless specially indicated, all amino acids referred to in this application are in the L-form.

“Unnatural amino acid” and “unnatural R-group” includes amino acids that are not naturally found in proteins. Examples of unnatural amino acids included herein are racemic mixtures of selenocysteine and selenomethionine. In addition, unnatural amino acids include the D or L forms of, for example, nor-leucine, para-nitrophenylalanine, homophenylalanine, para-fluorophenylalanine, 3-amino-2-benzylpropionic acid, homoarginines, D-phenylalanine, and the like.

“R-group” refers to the substituent attached to the α-carbon of an amino acid residue. An R-group is an important determinant of the overall chemical character of an amino acid. There are twenty natural R-groups found in proteins, which make up the twenty naturally occurring amino acids.

“α-carbon” refers to the chiral carbon atom found in an amino acid residue. Typically, four substituents will be covalently bound to said α-carbon including an amine group, a carboxylic acid group, a hydrogen atom, and an R-group.

“Positively charged amino acid” and “positively charged R-group” includes any naturally occurring or unnatural amino acid having a positively charged side chain under normal physiological conditions. Examples of positively charged, naturally occurring amino acids include arginine, lysine, histidine, and the like.

“Negatively charged amino acid” and “negatively charged R-group” includes any naturally occurring or unnatural amino acid having a negatively charged side chain under normal physiological conditions. Examples of negatively charged, naturally occurring amino acids include aspartic acid, glutamic acid, and the like.

“Hydrophobic amino acid” and “hydrophobic R-group” includes any naturally occurring or unnatural amino acid having an uncharged, nonpolar side chain that is relatively insoluble in water. Examples of naturally occurring hydrophobic amino acids are alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, methionine, and the like.

“Hydrophilic amino acid” and “hydrophilic R-group” includes any naturally occurring or unnatural amino acid having a charged polar side chain that is relatively soluble in water. Examples of naturally occurring hydrophilic amino acids include serine, threonine, tyrosine, asparagine, glutamine, cysteine, and the like.

“Mutant” or “mutated isomerase” refers to an isomerase enzyme (e.g., chalcone isomerase) having one or more R-group modifications to the amino acids of a wild-type isomerase or having a substitution of one or more amino acids, either conservative or non-conservative substitutions, that result in a modification to the catalytic activity of a wild-type isomerase. For example, a mutant isomerase has an R-group on one or more α-carbon other than the prescribed arrangements of R-groups associated with one or more α-carbon of a known isolated chalcone isomerase (Accession No. 1EYP, Protein Data Bank, Table 1, SEQ ID NOs:9-11). Access to the foregoing information in the Protein Data Bank can be found on the World Wide Web at the website for rcsb.org. Typically mutants refer to changes or modification to the configuration of R-groups within the active site, however mutations outside of the residues found in the active site are also considered to be mutants in light of the present invention.

“Nonmutated isomerase” includes an isomerase wherein no R-group(s) are changed relative to the active site of CHI (see, for example, PDB Accession No. 1EYP; and Table 1, SEQ ID NOs:9-11). A nonmutated isomerase according to the present invention may or may not have amino acid residues outside of the active site that are the same as those taught for native CHI (SEQ ID NO:1).

The R-groups of known isolated chalcone isomerases can be readily determined by consulting sequence databases well known in the art such as, for example, GenBank. Additional R-groups found inside and/or outside of the active site may or may not be the same. R-groups may be a natural R-group, unnatural R-group, hydrophobic R-group, hydrophilic R-group, positively charged R-group, negatively charged R-group, and the like.

“Non-native” or “non-native isomerase” refers to an isomerase protein that is not found in nature, whether isolated or not. A non-native isomerase may, for example, be a mutated isomerase (see, the Examples below).

“Native” or “native isomerase” refers to isomerase proteins that are produced in nature, e.g., are not mutated (see, for example, PDB Accession No. 1EYP, SEQ ID NOs:9-11).

“Purified” or “isolated” refers to a protein or nucleic acid, respectively, that has been separated from its natural environment Contaminant components of its natural environment may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In one embodiment, the isolated molecule, in the case of a protein, will be purified to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence or to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or silver stain. In the case of a nucleic acid the isolated molecule will preferably be purified to a degree sufficient to obtain a nucleic acid sequence using standard sequencing methods.

By a “substantially pure polypeptide” is meant an isomerase polypeptide (e.g., a chalcone isomerase) which has been separated from components which naturally accompany it. Typically, the polypeptide is substantially pure when it is at least 60%, by weight, free from the proteins and naturally-occurring organic molecules with which it is naturally associated. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, isomerase polypeptide. A substantially pure isomerase polypeptide may be obtained, for example, by extraction from a natural source; by expression of a recombinant nucleic acid encoding an isomerase polypeptide; or by chemically synthesizing the protein. Purity can be measured by any appropriate method (e.g., column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis).

“Degenerate variations thereof” refers to changing a gene sequence using the degenerate nature of the genetic code to encode proteins having the same amino acid sequence yet having a different gene sequence. For example, a chalcone isomerase of the present invention is based on amino acid sequences. Degenerate gene variations thereof can be made encoding the same protein due to the plasticity of the genetic code, as described herein.

“Expression” refers to transcription of a gene or nucleic acid sequence, stable accumulation of nucleic acid, and the translation of that nucleic acid to a polypeptide sequence. Expression of genes also involves transcription of the gene to make RNA, processing of RNA into mRNA in eukaryotic systems, and translation of mRNA into proteins. It is not necessary for the genes to integrate into the genome of a cell in order to achieve expression. This definition in no way limits expression to a particular system or to being confined to cells or a particular cell type and is meant to include cellular, transient, in vitro, in vivo, and viral expression systems in both prokaryotic, eukaryotic cells, and the like.

“Foreign” or “heterologous” genes refers to a gene encoding a protein whose exact amino acid sequence is not normally found in the host cell.

“Promoter” and “promoter regulatory element”, and the like, refers to a nucleotide sequence element within a nucleic acid fragment or gene that controls the expression of that gene. These can also include expression control sequences. Promoter regulatory elements, and the like, from a variety of sources can be used efficiently to promote gene expression. Promoter regulatory elements are meant to include constitutive, tissue-specific, developmental-specific, inducible, subgenomic promoters, and the like. Promoter regulatory elements may also include certain enhancer elements or silencing elements that improve or regulate transcriptional efficiency. Promoter regulatory elements are recognized by RNA polymerases, promote the binding thereof, and facilitate RNA transcription.

Table 1 lists the atomic structure coordinates for a chalcone isomerase (SEQ ID NOs:9-11) as derived by X-ray diffraction from a crystal of a chalcone isomerase. The data set, which may also be referred to as the “atomic coordinates” or “structure coordinates”, is useful for the methods of the present invention. In addition, invention methods may use a subset or portion of the atomic coordinates contained within this data set, for example, those atomic coordinates defining the amino acid residues which comprise the enzymatic active site. The following abbreviations are used in Table 1: “Atom Type” refers to the element whose coordinates are measured. The first letter in the column defines the element; “X, Y, Z” crystallographically define the atomic position of the element measured; “B” is a thermal factor that measures movement of the atom around its atomic center; and “molecule” denoted in the table refers to the particular monomer of CHI.

TABLE 1 Atom Atom Type Res # X Y Z OCC B Mol. 1 CB SER 4 1.314 23.727 49.727 1.00 67.92 A 2 OG SER 4 1.884 22.898 50.729 1.00 68.17 A 3 C SER 4 2.569 22.924 47.696 1.00 67.57 A 4 O SER 4 3.457 23.749 47.948 1.00 67.60 A 5 N SER 4 .637 21.623 48.600 1.00 67.80 A 6 CA SER 4 1.205 22.987 48.386 1.00 67.75 A 7 N ILE 5 2.718 21.924 46.829 1.00 67.22 A 8 CA ILE 5 3.933 21.713 46.044 1.00 66.80 A 9 CB ILE 5 4.100 20.197 45.707 1.00 66.89 A 10 CG2 ILE 5 2.735 19.531 45.616 1.00 66.97 A 11 CG1 ILE 5 4.885 20.005 44.408 1.00 66.89 A 12 CD1 ILE 5 6.348 20.312 44.527 1.00 66.95 A 13 C ILE 5 3.731 22.543 44.776 1.00 66.40 A 14 O ILE 5 2.987 22.154 43.877 1.00 66.38 A 15 N THR 6 4.382 23.700 44.723 1.00 65.89 A 16 CA THR 6 4.247 24.615 43.594 1.00 65.37 A 17 CB THR 6 4.518 26.068 44.030 1.00 65.36 A 18 OG1 THR 6 5.842 26.163 44.573 1.00 65.19 A 19 CG2 THR 6 3.510 26.509 45.078 1.00 65.29 A 20 C THR 6 5.149 24.331 42.402 1.00 65.02 A 21 O THR 6 5.990 23.432 42.429 1.00 64.94 A 22 N ALA 7 4.947 25.113 41.347 1.00 64.56 A 23 CA ALA 7 5.747 25.001 40.141 1.00 64.14 A 24 CB ALA 7 4.900 25.305 38.911 1.00 64.10 A 25 C ALA 7 6.848 26.040 40.294 1.00 63.80 A 26 O ALA 7 6.735 26.954 41.114 1.00 63.75 A 27 N ILE 8 7.917 25.894 39.524 1.00 63.43 A 28 CA ILE 8 9.020 26.841 39.589 1.00 63.05 A 29 CB ILE 8 10.269 26.220 40.250 1.00 62.98 A 30 CG2 ILE 8 11.387 27.252 40.320 1.00 62.92 A 31 CG1 ILE 8 9.926 25.724 41.654 1.00 62.91 A 32 CD1 ILE 8 11.064 25.002 42.332 1.00 62.85 A 33 C ILE 8 9.397 27.283 38.186 1.00 62.84 A 34 O ILE 8 9.495 26.467 37.272 1.00 62.74 A 35 N THR 9 9.598 28.581 38.015 1.00 62.62 A 36 CA THR 9 9.984 29.104 36.716 1.00 62.45 A 37 CB THR 9 9.017 30.206 36.235 1.00 62.45 A 38 OG1 THR 9 7.720 29.637 36.021 1.00 62.47 A 39 CG2 THR 9 9.505 30.817 34.928 1.00 62.44 A 40 C THR 9 11.393 29.664 36.802 1.00 62.27 A 41 O THR 9 11.708 30.455 37.689 1.00 62.24 A 42 N VAL 10 12.244 29.225 35.885 1.00 62.10 A 43 CA VAL 10 13.624 29.681 35.835 1.00 61.94 A 44 CB VAL 10 14.608 28.509 36.024 1.00 61.87 A 45 CG1 VAL 10 16.039 29.011 35.927 1.00 61.79 A 46 CG2 VAL 10 14.369 27.839 37.370 1.00 61.80 A 47 C VAL 10 13.863 30.310 34.469 1.00 61.89 A 48 O VAL 10 13.782 29.627 33.448 1.00 61.89 A 49 N GLU 11 14.148 31.608 34.453 1.00 61.82 A 50 CA GLU 11 14.390 32.314 33.201 1.00 61.74 A 51 CB GLU 11 15.757 31.931 32.634 1.00 61.91 A 52 CG GLU 11 16.926 32.601 33.322 1.00 62.24 A 53 CD GLU 11 16.947 34.102 33.095 1.00 62.41 A 54 OE1 GLU 11 16.966 34.530 31.919 1.00 62.59 A 55 OE2 GLU 11 16.944 34.851 34.093 1.00 62.48 A 56 C GLU 11 13.310 32.001 32.173 1.00 61.59 A 57 O GLU 11 13.609 31.632 31.039 1.00 61.66 A 58 N ASN 12 12.054 32.132 32.583 1.00 61.41 A 59 CA ASN 12 10.922 31.878 31.698 1.00 61.23 A 60 CB ASN 12 11.060 32.716 30.426 1.00 61.51 A 61 CG ASN 12 11.305 34.181 30.726 1.00 61.77 A 62 OD1 ASN 12 10.511 34.824 31.417 1.00 61.95 A 63 ND2 ASN 12 12.415 34.718 30.214 1.00 61.87 A 64 C ASN 12 10.728 30.408 31.330 1.00 60.92 A 65 O ASN 12 9.832 30.075 30.559 1.00 60.93 A 66 N LEU 13 11.576 29.536 31.865 1.00 60.46 A 67 CA LEU 13 11.451 28.103 31.612 1.00 60.03 A 68 CB LEU 13 12.832 27.448 31.513 1.00 59.92 A 69 CG LEU 13 13.692 27.886 30.326 1.00 59.82 A 70 CD1 LEU 13 15.112 27.380 30.496 1.00 59.84 A 71 CD2 LEU 13 13.082 27.359 29.041 1.00 59.83 A 72 C LEU 13 10.690 27.559 32.813 1.00 59.78 A 73 O LEU 13 11.206 27.551 33.930 1.00 59.74 A 74 N GLU 14 9.460 27.115 32.595 1.00 59.52 A 75 CA GLU 14 8.664 26.616 33.705 1.00 59.29 A 76 CB GLU 14 7.178 26.915 33.491 1.00 59.60 A 77 CG GLU 14 6.319 26.482 34.673 1.00 60.12 A 78 CD GLU 14 4.845 26.394 34.340 1.00 60.47 A 79 OE1 GLU 14 4.490 25.643 33.400 1.00 60.76 A 80 OE2 GLU 14 4.041 27.067 35.023 1.00 60.61 A 81 C GLU 14 8.818 25.133 33.989 1.00 58.89 A 82 O GLU 14 8.951 24.315 33.078 1.00 58.84 A 83 N TYR 15 8.796 24.811 35.276 1.00 58.40 A 84 CA TYR 15 8.894 23.442 35.750 1.00 58.01 A 85 CB TYR 15 10.107 23.270 36.663 1.00 57.57 A 86 CG TYR 15 11.404 23.193 35.903 1.00 57.20 A 87 CD1 TYR 15 11.998 24.336 35.373 1.00 56.96 A 88 CE1 TYR 15 13.172 24.256 34.631 1.00 56.83 A 89 CD2 TYR 15 12.017 21.964 35.674 1.00 56.98 A 90 CE2 TYR 15 13.186 21.870 34.934 1.00 56.81 A 91 CZ TYR 15 13.760 23.016 34.414 1.00 56.76 A 92 OH TYR 15 14.919 22.915 33.679 1.00 56.45 A 93 C TYR 15 7.618 23.132 36.516 1.00 57.93 A 94 O TYR 15 7.439 23.577 37.647 1.00 57.80 A 95 N PRO 16 6.703 22.379 35.891 1.00 57.97 A 96 CD PRO 16 6.811 21.806 34.539 1.00 57.95 A 97 CA PRO 16 5.429 22.005 36.514 1.00 58.06 A 98 CB PRO 16 4.829 21.029 35.505 1.00 58.00 A 99 CG PRO 16 5.373 21.514 34.206 1.00 58.02 A 100 C PRO 16 5.666 21.351 37.872 1.00 58.14 A 101 O PRO 16 6.686 20.694 38.081 1.00 58.11 A 102 N ALA 17 4.722 21.532 38.789 1.00 58.25 A 103 CA ALA 17 4.839 20.957 40.123 1.00 58.39 A 104 CB ALA 17 3.678 21.419 40.990 1.00 58.35 A 105 C ALA 17 4.872 19.435 40.067 1.00 58.46 A 106 O ALA 17 5.458 18.786 40.932 1.00 58.51 A 107 N VAL 18 4.242 18.872 39.045 1.00 58.58 A 108 CA VAL 18 4.183 17.425 38.882 1.00 58.75 A 109 CB VAL 18 2.849 16.865 39.448 1.00 58.76 A 110 CG1 VAL 18 2.686 15.402 39.079 1.00 58.85 A 111 CG2 VAL 18 2.821 17.025 40.957 1.00 58.73 A 112 C VAL 18 4.296 17.049 37.412 1.00 58.83 A 113 O VAL 18 3.944 17.835 36.535 1.00 58.87 A 114 N VAL 19 4.800 15.850 37.147 1.00 58.92 A 115 CA VAL 19 4.942 15.359 35.782 1.00 59.03 A 116 CB VAL 19 6.300 15.763 35.148 1.00 59.07 A 117 CG1 VAL 19 6.430 17.275 35.089 1.00 59.10 A 118 CG2 VAL 19 7.445 15.160 35.934 1.00 59.07 A 119 C VAL 19 4.863 13.841 35.794 1.00 59.13 A 120 O VAL 19 5.164 13.207 36.808 1.00 59.11 A 121 N THR 20 4.456 13.266 34.666 1.00 59.26 A 122 CA THR 20 4.350 11.817 34.529 1.00 59.38 A 123 CB THR 20 2.899 11.393 34.226 1.00 59.40 A 124 OG1 THR 20 2.067 11.731 35.342 1.00 59.47 A 125 CG2 THR 20 2.819 9.890 33.973 1.00 59.42 A 126 C THR 20 5.258 11.353 33.395 1.00 59.42 A 127 O THR 20 5.264 11.943 32.317 1.00 59.50 A 128 N SER 21 6.032 10.301 33.640 1.00 59.49 A 129 CA SER 21 6.943 9.784 32.625 1.00 59.51 A 130 CB SER 21 8.044 8.942 33.271 1.00 59.56 A 131 OG SER 21 8.853 8.329 32.277 1.00 59.58 A 132 C SER 21 6.247 8.942 31.566 1.00 59.51 A 133 O SER 21 5.539 7.989 31.884 1.00 59.49 A 134 N PRO 22 6.427 9.299 30.287 1.00 59.53 A 135 CD PRO 22 6.896 10.609 29.803 1.00 59.57 A 136 CA PRO 22 5.805 8.540 29.199 1.00 59.44 A 137 CB PRO 22 5.976 9.463 27.991 1.00 59.52 A 138 CG PRO 22 6.003 10.835 28.609 1.00 59.57 A 139 C PRO 22 6.576 7.232 29.029 1.00 59.35 A 140 O PRO 22 6.142 6.322 28.321 1.00 59.29 A 141 N VAL 23 7.722 7.152 29.701 1.00 59.24 A 142 CA VAL 23 8.586 5.980 29.632 1.00 59.12 A 143 CB VAL 23 10.076 6.383 29.781 1.00 59.16 A 144 CG1 VAL 23 10.967 5.150 29.690 1.00 59.11 A 145 CG2 VAL 23 10.450 7.400 28.709 1.00 59.19 A 146 C VAL 23 8.272 4.924 30.689 1.00 59.03 A 147 O VAL 23 8.253 3.731 30.393 1.00 59.06 A 148 N THR 24 8.019 5.362 31.918 1.00 58.90 A 149 CA THR 24 7.748 4.432 33.008 1.00 58.69 A 150 CB THR 24 8.759 4.636 34.150 1.00 58.76 A 151 OG1 THR 24 8.694 5.995 34.596 1.00 58.70 A 152 CG2 THR 24 10.174 4.327 33.678 1.00 58.73 A 153 C THR 24 6.345 4.544 33.595 1.00 58.51 A 154 O THR 24 5.917 3.675 34.356 1.00 58.54 A 155 N GLY 25 5.636 5.612 33.252 1.00 58.25 A 156 CA GLY 25 4.293 5.791 33.775 1.00 57.90 A 157 C GLY 25 4.290 6.303 35.205 1.00 57.62 A 158 O GLY 25 3.239 6.623 35.764 1.00 57.68 A 159 N LYS 26 5.472 6.383 35.805 1.00 57.25 A 160 CA LYS 26 5.592 6.862 37.174 1.00 56.78 A 161 CB LYS 26 6.977 6.513 37.720 1.00 56.84 A 162 CG LYS 26 7.244 5.014 37.718 1.00 56.94 A 163 CD LYS 26 8.619 4.652 38.255 1.00 57.05 A 164 CE LYS 26 8.748 3.143 38.402 1.00 57.13 A 165 NZ LYS 26 10.088 2.707 38.901 1.00 57.35 A 166 C LYS 26 5.354 8.368 37.224 1.00 56.40 A 167 O LYS 26 5.589 9.078 36.243 1.00 56.47 A 168 N SER 27 4.860 8.853 38.357 1.00 55.84 A 169 CA SER 27 4.607 10.282 38.512 1.00 55.24 A 170 CB SER 27 3.182 10.515 39.021 1.00 55.40 A 171 OG SER 27 2.947 9.774 40.205 1.00 55.82 A 172 C SER 27 5.619 10.866 39.491 1.00 54.61 A 173 O SER 27 6.023 10.197 40.443 1.00 54.55 A 174 N TYR 28 6.032 12.108 39.252 1.00 53.92 A 175 CA TYR 28 7.010 12.759 40.120 1.00 53.08 A 176 CB TYR 28 8.364 12.920 39.414 1.00 53.09 A 177 CG TYR 28 8.740 11.829 38.440 1.00 53.03 A 178 CD1 TYR 28 8.118 11.735 37.199 1.00 53.08 A 179 CE1 TYR 28 8.493 10.762 36.282 1.00 53.18 A 180 CD2 TYR 28 9.748 10.915 38.744 1.00 53.03 A 181 CE2 TYR 28 10.129 9.938 37.837 1.00 52.99 A 182 CZ TYR 28 9.500 9.867 36.608 1.00 53.14 A 183 OH TYR 28 9.874 8.908 35.701 1.00 53.23 A 184 C TYR 28 6.550 14.146 40.541 1.00 52.56 A 185 O TYR 28 5.671 14.743 39.916 1.00 52.53 A 186 N PHE 29 7.155 14.658 41.606 1.00 51.84 A 187 CA PHE 29 6.837 15.992 42.082 1.00 51.21 A 188 CB PHE 29 6.298 15.937 43.517 1.00 51.18 A 189 CG PHE 29 7.297 15.469 44.535 1.00 51.12 A 190 CD1 PHE 29 8.117 16.379 45.195 1.00 51.10 A 191 CD2 PHE 29 7.404 14.119 44.852 1.00 51.11 A 192 CE1 PHE 29 9.030 15.954 46.160 1.00 51.04 A 193 CE2 PHE 29 8.315 13.683 45.816 1.00 51.11 A 194 CZ PHE 29 9.129 14.604 46.471 1.00 51.04 A 195 C PHE 29 8.126 16.801 42.004 1.00 50.74 A 196 O PHE 29 9.218 16.260 42.184 1.00 50.60 A 197 N LEU 30 8.003 18.087 41.710 1.00 50.27 A 198 CA LEU 30 9.172 18.951 41.601 1.00 49.82 A 199 CB LEU 30 8.757 20.321 41.069 1.00 49.72 A 200 CG LEU 30 9.886 21.320 40.830 1.00 49.58 A 201 CD1 LEU 30 10.840 20.777 39.779 1.00 49.42 A 202 CD2 LEU 30 9.284 22.653 40.395 1.00 49.59 A 203 C LEU 30 9.874 19.111 42.945 1.00 49.54 A 204 O LEU 30 9.311 19.671 43.887 1.00 49.44 A 205 N GLY 31 11.106 18.613 43.024 1.00 49.23 A 206 CA GLY 31 11.866 18.724 44.257 1.00 48.92 A 207 C GLY 31 12.561 20.067 44.333 1.00 48.73 A 208 O GLY 31 12.777 20.617 45.414 1.00 48.72 A 209 N GLY 32 12.904 20.601 43.167 1.00 48.61 A 210 CA GLY 32 13.571 21.885 43.091 1.00 48.42 A 211 C GLY 32 14.033 22.199 41.681 1.00 48.30 A 212 O GLY 32 14.156 21.306 40.841 1.00 48.08 A 213 N ALA 33 14.278 23.479 41.422 1.00 48.27 A 214 CA ALA 33 14.738 23.938 40.118 1.00 48.30 A 215 CB ALA 33 13.553 24.384 39.266 1.00 48.18 A 216 C ALA 33 15.704 25.094 40.314 1.00 48.37 A 217 O ALA 33 15.560 25.884 41.247 1.00 48.48 A 218 N GLY 34 16.694 25.186 39.437 1.00 48.42 A 219 CA GLY 34 17.667 26.252 39.529 1.00 48.50 A 220 C GLY 34 18.320 26.486 38.181 1.00 48.60 A 221 O GLY 34 17.731 26.209 37.132 1.00 48.47 A 222 N GLU 35 19.550 26.984 38.208 1.00 48.66 A 223 CA GLU 35 20.268 27.255 36.980 1.00 48.81 A 224 CB GLU 35 20.173 28.731 36.625 1.00 49.27 A 225 CG GLU 35 19.336 29.521 37.593 1.00 50.31 A 226 CD GLU 35 19.328 30.995 37.273 1.00 50.76 A 227 OE1 GLU 35 19.983 31.383 36.294 1.00 51.26 A 228 OE2 GLU 35 18.668 31.766 37.995 1.00 51.30 A 229 C GLU 35 21.724 26.865 37.061 1.00 48.56 A 230 O GLU 35 22.319 26.835 38.137 1.00 48.49 A 231 N ARG 36 22.294 26.557 35.906 1.00 48.31 A 232 CA ARG 36 23.692 26.184 35.814 1.00 48.10 A 233 CB ARG 36 23.834 24.681 35.559 1.00 48.15 A 234 CG ARG 36 24.466 23.912 36.716 1.00 48.32 A 235 CD ARG 36 23.936 24.429 38.027 1.00 48.33 A 236 NE ARG 36 23.980 23.448 39.103 1.00 48.32 A 237 CZ ARG 36 23.172 23.506 40.153 1.00 48.28 A 238 NH1 ARG 36 22.287 24.492 40.229 1.00 48.19 A 239 NH2 ARG 36 23.239 22.590 41.114 1.00 48.15 A 240 C ARG 36 24.256 26.954 34.648 1.00 48.05 A 241 O ARG 36 23.530 27.321 33.721 1.00 47.90 A 242 N GLY 37 25.553 27.201 34.706 1.00 47.95 A 243 CA GLY 37 26.202 27.934 33.646 1.00 47.99 A 244 C GLY 37 27.680 27.972 33.926 1.00 47.99 A 245 O GLY 37 28.225 27.045 34.519 1.00 47.95 A 246 N LEU 38 28.328 29.052 33.510 1.00 47.97 A 247 CA LEU 38 29.757 29.190 33.723 1.00 47.98 A 248 CB LEU 38 30.497 29.063 32.382 1.00 48.09 A 249 CG LEU 38 30.242 27.777 31.580 1.00 48.20 A 250 CD1 LEU 38 30.780 27.914 30.165 1.00 48.09 A 251 CD2 LEU 38 30.894 26.601 32.287 1.00 48.21 A 252 C LEU 38 30.071 30.533 34.361 1.00 47.94 A 253 O LEU 38 29.368 31.521 34.145 1.00 47.77 A 254 N THR 39 31.114 30.554 35.178 1.00 47.97 A 255 CA THR 39 31.544 31.794 35.797 1.00 48.05 A 256 CB THR 39 32.021 31.579 37.242 1.00 48.08 A 257 OG1 THR 39 30.921 31.111 38.030 1.00 48.06 A 258 CG2 THR 39 32.532 32.894 37.839 1.00 48.01 A 259 C THR 39 32.697 32.254 34.919 1.00 48.04 A 260 O THR 39 33.765 31.642 34.902 1.00 48.00 A 261 N ILE 40 32.452 33.313 34.160 1.00 48.10 A 262 CA ILE 40 33.452 33.854 33.249 1.00 48.20 A 263 CB ILE 40 32.884 33.983 31.816 1.00 48.29 A 264 CG2 ILE 40 33.992 34.369 30.856 1.00 48.42 A 265 CG1 ILE 40 32.241 32.664 31.372 1.00 48.43 A 266 CD1 ILE 40 33.229 31.523 31.159 1.00 48.46 A 267 C ILE 40 33.858 35.241 33.732 1.00 48.15 A 268 O ILE 40 33.030 36.156 33.785 1.00 48.07 A 269 N GLU 41 35.131 35.389 34.085 1.00 48.08 A 270 CA GLU 41 35.644 36.665 34.569 1.00 47.96 A 271 CB GLU 41 35.594 37.711 33.450 1.00 48.36 A 272 CG GLU 41 36.387 37.321 32.207 1.00 48.95 A 273 CD GLU 41 37.889 37.463 32.393 1.00 49.41 A 274 OE1 GLU 41 38.413 36.986 33.424 1.00 49.70 A 275 OE2 GLU 41 38.549 38.051 31.502 1.00 49.86 A 276 C GLU 41 34.816 37.137 35.754 1.00 47.62 A 277 O GLU 41 34.394 38.290 35.804 1.00 47.61 A 278 N GLY 42 34.575 36.234 36.700 1.00 47.21 A 279 CA GLY 42 33.805 36.586 37.881 1.00 46.69 A 280 C GLY 42 32.329 36.848 37.638 1.00 46.35 A 281 O GLY 42 31.622 37.266 38.555 1.00 46.46 A 282 N ASN 43 31.861 36.603 36.415 1.00 45.84 A 283 CA ASN 43 30.458 36.809 36.057 1.00 45.29 A 284 CB ASN 43 30.349 37.654 34.786 1.00 45.16 A 285 CG ASN 43 30.617 39.121 35.035 1.00 45.00 A 286 OD1 ASN 43 29.693 39.899 35.273 1.00 44.96 A 287 ND2 ASN 43 31.886 39.506 34.990 1.00 44.74 A 288 C ASN 43 29.760 35.479 35.813 1.00 45.05 A 289 O ASN 43 30.271 34.628 35.083 1.00 44.95 A 290 N PHE 44 28.592 35.296 36.421 1.00 44.77 A 291 CA PHE 44 27.856 34.062 36.218 1.00 44.54 A 292 CB PHE 44 26.857 33.801 37.345 1.00 44.68 A 293 CG PHE 44 26.102 32.502 37.187 1.00 44.83 A 294 CD1 PHE 44 26.780 31.286 37.185 1.00 44.87 A 295 CD2 PHE 44 24.719 32.496 37.048 1.00 44.98 A 296 CE1 PHE 44 26.092 30.079 37.050 1.00 45.03 A 297 CE2 PHE 44 24.019 31.298 36.914 1.00 45.00 A 298 CZ PHE 44 24.708 30.084 36.915 1.00 45.08 A 299 C PHE 44 27.100 34.142 34.904 1.00 44.28 A 300 O PHE 44 26.204 34.968 34.739 1.00 44.16 A 301 N ILE 45 27.477 33.284 33.967 1.00 44.04 A 302 CA ILE 45 26.825 33.245 32.670 1.00 43.98 A 303 CB ILE 45 27.867 33.142 31.535 1.00 43.86 A 304 CG2 ILE 45 27.179 33.253 30.171 1.00 43.72 A 305 CG1 ILE 45 28.915 34.253 31.697 1.00 43.65 A 306 CD1 ILE 45 28.339 35.658 31.718 1.00 43.39 A 307 C ILE 45 25.924 32.016 32.678 1.00 44.04 A 308 O ILE 45 26.402 30.882 32.703 1.00 43.96 A 309 N LYS 46 24.620 32.260 32.685 1.00 44.19 A 310 CA LYS 46 23.632 31.191 32.713 1.00 44.41 A 311 CB LYS 46 22.255 31.745 33.069 1.00 44.81 A 312 CG LYS 46 22.226 32.729 34.226 1.00 45.69 A 313 CD LYS 46 20.797 33.163 34.535 1.00 46.28 A 314 CE LYS 46 20.057 33.662 33.294 1.00 46.83 A 315 NZ LYS 46 20.028 35.167 33.162 1.00 47.55 A 316 C LYS 46 23.540 30.499 31.359 1.00 44.31 A 317 O LYS 46 23.489 31.161 30.326 1.00 44.22 A 318 N PHE 47 23.517 29.169 31.376 1.00 44.11 A 319 CA PHE 47 23.410 28.391 30.151 1.00 44.14 A 320 CB PHE 47 24.660 27.550 29.933 1.00 43.96 A 321 CG PHE 47 25.743 28.279 29.203 1.00 44.12 A 322 CD1 PHE 47 26.644 29.092 29.888 1.00 44.02 A 323 CD2 PHE 47 25.827 28.201 27.815 1.00 44.07 A 324 CE1 PHE 47 27.611 29.817 29.200 1.00 43.92 A 325 CE2 PHE 47 26.791 28.923 27.116 1.00 43.99 A 326 CZ PHE 47 27.686 29.735 27.811 1.00 43.99 A 327 C PHE 47 22.194 27.484 30.150 1.00 44.13 A 328 O PHE 47 21.664 27.152 29.086 1.00 44.05 A 329 N THR 48 21.743 27.077 31.330 1.00 44.21 A 330 CA THR 48 20.590 26.200 31.393 1.00 44.44 A 331 CB THR 48 21.002 24.726 31.133 1.00 44.49 A 332 OG1 THR 48 19.824 23.910 31.060 1.00 44.77 A 333 CG2 THR 48 21.902 24.200 32.253 1.00 44.35 A 334 C THR 48 19.835 26.247 32.702 1.00 44.49 A 335 O THR 48 20.341 26.708 33.728 1.00 44.53 A 336 N ALA 49 18.596 25.789 32.643 1.00 44.62 A 337 CA ALA 49 17.757 25.700 33.819 1.00 44.66 A 338 CB ALA 49 16.326 26.106 33.502 1.00 44.62 A 339 C ALA 49 17.821 24.218 34.149 1.00 44.73 A 340 O ALA 49 18.098 23.387 33.277 1.00 44.64 A 341 N ILE 50 17.605 23.888 35.409 1.00 44.80 A 342 CA ILE 50 17.630 22.501 35.823 1.00 45.04 A 343 CB ILE 50 18.963 22.098 36.472 1.00 45.43 A 344 CG2 ILE 50 18.916 20.618 36.842 1.00 45.46 A 345 CG1 ILE 50 20.117 22.339 35.504 1.00 45.85 A 346 CD1 ILE 50 21.468 22.096 36.128 1.00 46.32 A 347 C ILE 50 16.547 22.281 36.849 1.00 44.88 A 348 O ILE 50 16.352 23.097 37.749 1.00 44.85 A 349 N GLY 51 15.841 21.174 36.700 1.00 44.82 A 350 CA GLY 51 14.792 20.836 37.637 1.00 44.61 A 351 C GLY 51 14.951 19.380 38.020 1.00 44.59 A 352 O GLY 51 15.251 18.535 37.175 1.00 44.53 A 353 N VAL 52 14.772 19.086 39.301 1.00 44.48 A 354 CA VAL 52 14.881 17.721 39.780 1.00 44.45 A 355 CB VAL 52 15.888 17.607 40.936 1.00 44.45 A 356 CG1 VAL 52 15.957 16.162 41.424 1.00 44.49 A 357 CG2 VAL 52 17.257 18.077 40.475 1.00 44.55 A 358 C VAL 52 13.527 17.233 40.267 1.00 44.39 A 359 O VAL 52 12.932 17.822 41.170 1.00 44.42 A 360 N TYR 53 13.035 16.267 39.649 1.00 44.36 A 361 CA TYR 53 11.764 15.585 40.053 1.00 44.38 A 362 CB TYR 53 10.873 15.298 38.841 1.00 44.42 A 363 CG TYR 53 10.307 16.543 38.209 1.00 44.64 A 364 CD1 TYR 53 11.004 17.218 37.211 1.00 44.66 A 365 CE1 TYR 53 10.510 18.392 36.656 1.00 44.85 A 366 CD2 TYR 53 9.091 17.075 38.642 1.00 44.79 A 367 CE2 TYR 53 8.585 18.256 38.093 1.00 44.84 A 368 CZ TYR 53 9.300 18.906 37.102 1.00 44.90 A 369 OH TYR 53 8.814 20.070 36.550 1.00 44.98 A 370 C TYR 53 12.019 14.294 40.809 1.00 44.31 A 371 O TYR 53 12.924 13.535 40.473 1.00 44.16 A 372 N LEU 54 11.222 14.057 41.842 1.00 44.38 A 373 CA LEU 54 11.360 12.846 42.630 1.00 44.58 A 374 CB LEU 54 11.602 13.196 44.098 1.00 44.57 A 375 CG LEU 54 12.821 14.066 44.413 1.00 44.65 A 376 CD1 LEU 54 12.956 14.179 45.920 1.00 44.61 A 377 CD2 LEU 54 14.081 13.457 43.814 1.00 44.54 A 378 C LEU 54 10.067 12.055 42.488 1.00 44.72 A 379 O LEU 54 8.980 12.634 42.499 1.00 44.65 A 380 N GLU 55 10.182 10.740 42.340 1.00 44.92 A 381 CA GLU 55 8.999 9.905 42.202 1.00 45.23 A 382 CB GLU 55 9.388 8.429 42.108 1.00 45.30 A 383 CG GLU 55 8.289 7.553 41.512 1.00 45.53 A 384 CD GLU 55 8.682 6.094 41.412 1.00 45.70 A 385 OE1 GLU 55 9.897 5.791 41.434 1.00 45.76 A 386 OE2 GLU 55 7.773 5.245 41.297 1.00 45.91 A 387 C GLU 55 8.118 10.141 43.422 1.00 45.38 A 388 O GLU 55 8.619 10.341 44.528 1.00 45.30 A 389 N ASP 56 6.805 10.133 43.221 1.00 45.67 A 390 CA ASP 56 5.875 10.365 44.320 1.00 45.96 A 391 CB ASP 56 4.433 10.122 43.847 1.00 46.66 A 392 CG ASP 56 4.256 8.790 43.135 1.00 47.25 A 393 OD1 ASP 56 3.175 8.582 42.539 1.00 47.89 A 394 OD2 ASP 56 5.180 7.946 43.162 1.00 47.80 A 395 C ASP 56 6.178 9.531 45.565 1.00 45.79 A 396 O ASP 56 6.049 10.014 46.690 1.00 45.83 A 397 N ILE 57 6.605 8.290 45.371 1.00 45.59 A 398 CA ILE 57 6.904 7.422 46.505 1.00 45.50 A 399 CB ILE 57 7.136 5.975 46.039 1.00 45.50 A 400 CG2 ILE 57 5.880 5.456 45.326 1.00 45.59 A 401 CG1 ILE 57 8.342 5.915 45.097 1.00 45.25 A 402 CD1 ILE 57 8.695 4.520 44.636 1.00 45.00 A 403 C ILE 57 8.107 7.875 47.339 1.00 45.50 A 404 O ILE 57 8.345 7.355 48.428 1.00 45.45 A 405 N ALA 58 8.861 8.847 46.837 1.00 45.47 A 406 CA ALA 58 10.025 9.338 47.569 1.00 45.46 A 407 CB ALA 58 10.709 10.441 46.777 1.00 45.36 A 408 C ALA 58 9.636 9.852 48.956 1.00 45.54 A 409 O ALA 58 10.403 9.735 49.915 1.00 45.38 A 410 N VAL 59 8.433 10.414 49.053 1.00 45.66 A 411 CA VAL 59 7.933 10.963 50.310 1.00 45.90 A 412 CB VAL 59 6.510 11.543 50.125 1.00 45.96 A 413 CG1 VAL 59 6.036 12.200 51.414 1.00 46.02 A 414 CG2 VAL 59 6.513 12.547 48.981 1.00 46.03 A 415 C VAL 59 7.911 9.917 51.418 1.00 45.95 A 416 O VAL 59 8.474 10.132 52.493 1.00 46.04 A 417 N ALA 60 7.259 8.789 51.156 1.00 46.03 A 418 CA ALA 60 7.176 7.706 52.132 1.00 46.13 A 419 CB ALA 60 6.321 6.570 51.576 1.00 46.10 A 420 C ALA 60 8.567 7.181 52.487 1.00 46.26 A 421 O ALA 60 8.842 6.844 53.642 1.00 46.27 A 422 N SER 61 9.441 7.105 51.487 1.00 46.37 A 423 CA SER 61 10.800 6.613 51.695 1.00 46.45 A 424 CB SER 61 11.505 6.442 50.348 1.00 46.27 A 425 OG SER 61 12.858 6.065 50.529 1.00 45.97 A 426 C SER 61 11.634 7.534 52.584 1.00 46.70 A 427 O SER 61 12.381 7.074 53.445 1.00 46.61 A 428 N LEU 62 11.504 8.838 52.366 1.00 47.06 A 429 CA LEU 62 12.264 9.824 53.124 1.00 47.50 A 430 CB LEU 62 12.423 11.094 52.281 1.00 47.29 A 431 CG LEU 62 13.216 10.963 50.974 1.00 47.14 A 432 CD1 LEU 62 12.898 12.134 50.065 1.00 47.11 A 433 CD2 LEU 62 14.707 10.901 51.269 1.00 47.05 A 434 C LEU 62 11.645 10.181 54.475 1.00 47.94 A 435 O LEU 62 12.342 10.636 55.382 1.00 47.96 A 436 N ALA 63 10.341 9.959 54.606 1.00 48.47 A 437 CA ALA 63 9.609 10.281 55.829 1.00 49.01 A 438 CB ALA 63 8.182 9.738 55.735 1.00 48.91 A 439 C ALA 63 10.248 9.812 57.134 1.00 49.39 A 440 O ALA 63 10.470 10.619 58.043 1.00 49.51 A 441 N ALA 64 10.545 8.523 57.227 1.00 49.79 A 442 CA ALA 64 11.123 7.954 58.441 1.00 50.27 A 443 CB ALA 64 11.583 6.537 58.170 1.00 50.33 A 444 C ALA 64 12.273 8.767 59.020 1.00 50.57 A 445 O ALA 64 12.213 9.230 60.164 1.00 50.74 A 446 N LYS 65 13.314 8.954 58.226 1.00 50.78 A 447 CA LYS 65 14.484 9.686 58.684 1.00 51.02 A 448 CB LYS 65 15.705 9.308 57.832 1.00 50.84 A 449 CG LYS 65 16.145 7.871 57.945 1.00 50.72 A 450 CD LYS 65 17.253 7.556 56.959 1.00 50.55 A 451 CE LYS 65 18.469 8.455 57.174 1.00 50.54 A 452 NZ LYS 65 19.582 8.084 56.260 1.00 50.34 A 453 C LYS 65 14.371 11.204 58.691 1.00 51.29 A 454 O LYS 65 15.004 11.858 59.510 1.00 51.21 A 455 N TRP 66 13.559 11.768 57.803 1.00 51.71 A 456 CA TRP 66 13.510 13.224 57.702 1.00 52.27 A 457 CB TRP 66 13.947 13.625 56.284 1.00 52.00 A 458 CG TRP 66 15.219 12.925 55.918 1.00 51.86 A 459 CD2 TRP 66 16.500 13.127 56.532 1.00 51.78 A 460 CE2 TRP 66 17.380 12.174 55.983 1.00 51.69 A 461 CE3 TRP 66 16.983 14.018 57.494 1.00 51.76 A 462 CD1 TRP 66 15.376 11.897 55.039 1.00 51.80 A 463 NE1 TRP 66 16.676 11.435 55.075 1.00 51.70 A 464 CZ2 TRP 66 18.720 12.086 56.368 1.00 51.68 A 465 CZ3 TRP 66 18.316 13.928 57.878 1.00 51.76 A 466 CH2 TRP 66 19.166 12.964 57.310 1.00 51.70 A 467 C TRP 66 12.265 14.000 58.099 1.00 52.82 A 468 O TRP 66 12.299 15.230 58.109 1.00 52.83 A 469 N LYS 67 11.172 13.321 58.418 1.00 53.49 A 470 CA LYS 67 9.981 14.049 58.824 1.00 54.21 A 471 CB LYS 67 8.819 13.085 59.067 1.00 54.43 A 472 CG LYS 67 7.514 13.802 59.389 1.00 54.89 A 473 CD LYS 67 6.372 12.831 59.655 1.00 55.21 A 474 CE LYS 67 5.123 13.565 60.154 1.00 55.51 A 475 NZ LYS 67 4.004 12.622 60.451 1.00 55.72 A 476 C LYS 67 10.302 14.817 60.107 1.00 54.57 A 477 O LYS 67 11.158 14.397 60.888 1.00 54.62 A 478 N GLY 68 9.633 15.945 60.313 1.00 54.97 A 479 CA GLY 68 9.881 16.714 61.517 1.00 55.48 A 480 C GLY 68 11.142 17.567 61.493 1.00 55.79 A 481 O GLY 68 11.321 18.427 62.351 1.00 55.94 A 482 N LYS 69 12.024 17.344 60.528 1.00 56.06 A 483 CA LYS 69 13.254 18.128 60.433 1.00 56.28 A 484 CB LYS 69 14.303 17.396 59.586 1.00 56.40 A 485 CG LYS 69 14.711 16.012 60.072 1.00 56.61 A 486 CD LYS 69 15.423 16.035 61.404 1.00 56.82 A 487 CE LYS 69 16.014 14.669 61.680 1.00 56.88 A 488 NZ LYS 69 14.926 13.657 61.657 1.00 57.06 A 489 C LYS 69 12.947 19.472 59.773 1.00 56.39 A 490 O LYS 69 12.129 19.539 58.854 1.00 56.43 A 491 N SER 70 13.599 20.539 60.224 1.00 56.49 A 492 CA SER 70 13.356 21.849 59.627 1.00 56.59 A 493 CB SER 70 13.750 22.963 60.596 1.00 56.59 A 494 OG SER 70 15.159 23.074 60.709 1.00 56.59 A 495 C SER 70 14.163 21.992 58.336 1.00 56.69 A 496 O SER 70 15.172 21.303 58.149 1.00 56.70 A 497 N SER 71 13.722 22.883 57.450 1.00 56.67 A 498 CA SER 71 14.433 23.106 56.193 1.00 56.71 A 499 CB SER 71 13.802 24.252 55.401 1.00 56.61 A 500 OG SER 71 12.457 23.959 55.072 1.00 56.71 A 501 C SER 71 15.888 23.440 56.476 1.00 56.73 A 502 O SER 71 16.792 22.941 55.805 1.00 56.77 A 503 N GLU 72 16.107 24.277 57.483 1.00 56.79 A 504 CA GLU 72 17.450 24.693 57.849 1.00 56.88 A 505 CB GLU 72 17.402 25.690 59.012 1.00 57.38 A 506 CG GLU 72 16.430 26.852 58.823 1.00 58.18 A 507 CD GLU 72 14.973 26.428 58.943 1.00 58.60 A 508 OE1 GLU 72 14.677 25.517 59.756 1.00 59.03 A 509 OE2 GLU 72 14.113 27.010 58.239 1.00 58.90 A 510 C GLU 72 18.281 23.479 58.246 1.00 56.65 A 511 O GLU 72 19.474 23.402 57.934 1.00 56.67 A 512 N GLU 73 17.645 22.534 58.931 1.00 56.31 A 513 CA GLU 73 18.327 21.321 59.373 1.00 55.99 A 514 CB GLU 73 17.479 20.596 60.411 1.00 56.34 A 515 CG GLU 73 18.198 19.447 61.076 1.00 56.94 A 516 CD GLU 73 17.366 18.786 62.153 1.00 57.34 A 517 OE1 GLU 73 16.262 19.308 62.478 1.00 57.53 A 518 OE2 GLU 73 17.826 17.741 62.678 1.00 57.51 A 519 C GLU 73 18.623 20.382 58.204 1.00 55.46 A 520 O GLU 73 19.726 19.846 58.093 1.00 55.44 A 521 N LEU 74 17.640 20.188 57.332 1.00 54.85 A 522 CA LEU 74 17.834 19.320 56.179 1.00 54.21 A 523 CB LEU 74 16.557 19.230 55.341 1.00 54.21 A 524 CG LEU 74 15.374 18.505 55.982 1.00 54.26 A 525 CD1 LEU 74 14.218 18.545 55.015 1.00 54.12 A 526 CD2 LEU 74 15.741 17.073 56.313 1.00 54.10 A 527 C LEU 74 18.966 19.869 55.327 1.00 53.75 A 528 O LEU 74 19.890 19.141 54.975 1.00 53.62 A 529 N LEU 75 18.917 21.165 55.041 1.00 53.20 A 530 CA LEU 75 19.934 21.792 54.203 1.00 52.62 A 531 CB LEU 75 19.693 23.306 54.085 1.00 52.66 A 532 CG LEU 75 20.678 24.078 53.193 1.00 52.68 A 533 CD1 LEU 75 20.657 23.565 51.765 1.00 52.54 A 534 CD2 LEU 75 20.293 25.542 53.215 1.00 52.73 A 535 C LEU 75 21.367 21.539 54.654 1.00 52.18 A 536 O LEU 75 22.246 21.360 53.821 1.00 52.13 A 537 N GLU 76 21.604 21.498 55.960 1.00 51.70 A 538 CA GLU 76 22.960 21.288 56.468 1.00 51.14 A 539 CB GLU 76 23.139 22.025 57.805 1.00 51.69 A 540 CG GLU 76 22.263 21.456 58.919 1.00 52.39 A 541 CD GLU 76 22.485 22.120 60.274 1.00 52.91 A 542 OE1 GLU 76 23.297 23.078 60.349 1.00 53.16 A 543 OE2 GLU 76 21.840 21.683 61.267 1.00 53.17 A 544 C GLU 76 23.295 19.810 56.670 1.00 50.46 A 545 O GLU 76 24.387 19.481 57.134 1.00 50.48 A 546 N THR 77 22.376 18.916 56.316 1.00 49.52 A 547 CA THR 77 22.608 17.482 56.517 1.00 48.55 A 548 CB THR 77 21.393 16.832 57.210 1.00 48.64 A 549 OG1 THR 77 21.011 17.623 58.341 1.00 48.63 A 550 CG2 THR 77 21.737 15.424 57.678 1.00 48.51 A 551 C THR 77 22.905 16.709 55.232 1.00 47.86 A 552 O THR 77 21.999 16.427 54.447 1.00 47.69 A 553 N LEU 78 24.176 16.369 55.026 1.00 46.95 A 554 CA LEU 78 24.590 15.635 53.835 1.00 46.11 A 555 CB LEU 78 26.095 15.337 53.877 1.00 46.00 A 556 CG LEU 78 27.036 16.539 53.810 1.00 45.95 A 557 CD1 LEU 78 28.458 16.058 53.908 1.00 45.93 A 558 CD2 LEU 78 26.831 17.293 52.524 1.00 45.83 A 559 C LEU 78 23.825 14.322 53.664 1.00 45.56 A 560 O LEU 78 23.487 13.936 52.548 1.00 45.41 A 561 N ASP 79 23.553 13.646 54.775 1.00 44.78 A 562 CA ASP 79 22.845 12.377 54.739 1.00 44.19 A 563 CB ASP 79 22.620 11.853 56.160 1.00 44.07 A 564 CG ASP 79 22.214 10.395 56.183 1.00 43.85 A 565 OD1 ASP 79 21.292 10.057 56.945 1.00 43.81 A 566 OD2 ASP 79 22.827 9.591 55.452 1.00 43.55 A 567 C ASP 79 21.507 12.534 54.029 1.00 43.87 A 568 O ASP 79 21.081 11.650 53.287 1.00 43.79 A 569 N PHE 80 20.847 13.663 54.268 1.00 43.46 A 570 CA PHE 80 19.559 13.946 53.649 1.00 43.12 A 571 CB PHE 80 19.080 15.339 54.050 1.00 43.22 A 572 CG PHE 80 17.830 15.779 53.339 1.00 43.41 A 573 CD1 PHE 80 17.794 17.000 52.664 1.00 43.41 A 574 CD2 PHE 80 16.686 14.984 53.355 1.00 43.40 A 575 CE1 PHE 80 16.633 17.428 52.011 1.00 43.56 A 576 CE2 PHE 80 15.517 15.397 52.707 1.00 43.61 A 577 CZ PHE 80 15.490 16.624 52.033 1.00 43.59 A 578 C PHE 80 19.677 13.870 52.131 1.00 42.88 A 579 O PHE 80 18.904 13.168 51.463 1.00 42.77 A 580 N TYR 81 20.652 14.592 51.591 1.00 42.41 A 581 CA TYR 81 20.863 14.605 50.156 1.00 42.04 A 582 CB TYR 81 21.844 15.722 49.789 1.00 42.05 A 583 CG TYR 81 21.238 17.071 50.098 1.00 42.06 A 584 CD1 TYR 81 21.532 17.740 51.288 1.00 42.06 A 585 CE1 TYR 81 20.858 18.913 51.637 1.00 42.06 A 586 CD2 TYR 81 20.262 17.615 49.261 1.00 41.96 A 587 CE2 TYR 81 19.587 18.776 49.598 1.00 41.95 A 588 CZ TYR 81 19.884 19.421 50.785 1.00 42.02 A 589 OH TYR 81 19.190 20.562 51.121 1.00 42.06 A 590 C TYR 81 21.316 13.254 49.635 1.00 41.73 A 591 O TYR 81 21.047 12.914 48.484 1.00 41.56 A 592 N ARG 82 21.989 12.472 50.476 1.00 41.49 A 593 CA ARG 82 22.416 11.146 50.043 1.00 41.39 A 594 CB ARG 82 23.368 10.501 51.053 1.00 41.56 A 595 CG ARG 82 24.743 11.152 51.094 1.00 41.85 A 596 CD ARG 82 25.827 10.159 51.476 1.00 41.94 A 597 NE ARG 82 27.135 10.810 51.497 1.00 42.20 A 598 CZ ARG 82 27.610 11.489 52.535 1.00 42.16 A 599 NH1 ARG 82 26.889 11.597 53.642 1.00 42.08 A 600 NH2 ARG 82 28.798 12.079 52.456 1.00 42.21 A 601 C ARG 82 21.189 10.261 49.861 1.00 41.18 A 602 O ARG 82 21.137 9.456 48.935 1.00 41.19 A 603 N ASP 83 20.207 10.405 50.745 1.00 40.88 A 604 CA ASP 83 18.989 9.610 50.631 1.00 40.73 A 605 CB ASP 83 18.086 9.794 51.848 1.00 40.55 A 606 CG ASP 83 18.582 9.036 53.055 1.00 40.56 A 607 OD1 ASP 83 19.253 8.002 52.869 1.00 40.49 A 608 OD2 ASP 83 18.289 9.464 54.189 1.00 40.67 A 609 C ASP 83 18.236 10.017 49.377 1.00 40.62 A 610 O ASP 83 17.642 9.182 48.709 1.00 40.71 A 611 N ILE 84 18.259 11.303 49.055 1.00 40.36 A 612 CA ILE 84 17.582 11.765 47.857 1.00 40.35 A 613 CB ILE 84 17.556 13.302 47.774 1.00 40.35 A 614 CG2 ILE 84 17.102 13.737 46.387 1.00 40.17 A 615 CG1 ILE 84 16.619 13.860 48.840 1.00 40.41 A 616 CD1 ILE 84 16.633 15.367 48.925 1.00 40.76 A 617 C ILE 84 18.278 11.238 46.607 1.00 40.24 A 618 O ILE 84 17.624 10.773 45.669 1.00 40.39 A 619 N ILE 85 19.605 11.309 46.598 1.00 39.99 A 620 CA ILE 85 20.393 10.872 45.454 1.00 39.77 A 621 CB ILE 85 21.885 11.237 45.632 1.00 39.66 A 622 CG2 ILE 85 22.722 10.612 44.517 1.00 39.42 A 623 CG1 ILE 85 22.051 12.762 45.654 1.00 39.65 A 624 CD1 ILE 85 23.433 13.217 46.110 1.00 39.43 A 625 C ILE 85 20.306 9.377 45.202 1.00 39.75 A 626 O ILE 85 20.106 8.936 44.067 1.00 39.69 A 627 N SER 86 20.458 8.600 46.266 1.00 39.72 A 628 CA SER 86 20.446 7.149 46.152 1.00 39.80 A 629 CB SER 86 21.688 6.589 46.841 1.00 39.86 A 630 OG SER 86 22.853 7.094 46.221 1.00 40.14 A 631 C SER 86 19.209 6.478 46.725 1.00 39.65 A 632 O SER 86 19.219 5.278 46.986 1.00 39.70 A 633 N GLY 87 18.148 7.251 46.917 1.00 39.62 A 634 CA GLY 87 16.922 6.701 47.468 1.00 39.42 A 635 C GLY 87 16.271 5.701 46.537 1.00 39.31 A 636 O GLY 87 16.462 5.760 45.323 1.00 39.13 A 637 N PRO 88 15.490 4.762 47.089 1.00 39.33 A 638 CD PRO 88 15.214 4.644 48.532 1.00 39.36 A 639 CA PRO 88 14.787 3.719 46.342 1.00 39.36 A 640 CB PRO 88 14.417 2.723 47.435 1.00 39.34 A 641 CG PRO 88 14.090 3.626 48.575 1.00 39.38 A 642 C PRO 88 13.568 4.264 45.603 1.00 39.39 A 643 O PRO 88 12.429 3.862 45.851 1.00 39.44 A 644 N PHE 89 13.814 5.200 44.700 1.00 39.46 A 645 CA PHE 89 12.755 5.799 43.909 1.00 39.53 A 646 CB PHE 89 11.944 6.787 44.753 1.00 39.50 A 647 CG PHE 89 12.782 7.703 45.591 1.00 39.55 A 648 CD1 PHE 89 13.426 8.803 45.020 1.00 39.59 A 649 CD2 PHE 89 12.937 7.465 46.957 1.00 39.49 A 650 CE1 PHE 89 14.211 9.653 45.796 1.00 39.50 A 651 CE2 PHE 89 13.723 8.309 47.745 1.00 39.56 A 652 CZ PHE 89 14.362 9.409 47.156 1.00 39.51 A 653 C PHE 89 13.394 6.486 42.721 1.00 39.68 A 654 O PHE 89 14.564 6.878 42.764 1.00 39.78 A 655 N GLU 90 12.631 6.623 41.651 1.00 39.59 A 656 CA GLU 90 13.148 7.230 40.449 1.00 39.72 A 657 CB GLU 90 12.242 6.863 39.281 1.00 39.81 A 658 CG GLU 90 12.930 6.874 37.953 1.00 40.17 A 659 CD GLU 90 12.091 6.233 36.879 1.00 40.25 A 660 OE1 GLU 90 11.068 6.830 36.495 1.00 40.45 A 661 OE2 GLU 90 12.453 5.131 36.424 1.00 40.31 A 662 C GLU 90 13.265 8.740 40.574 1.00 39.72 A 663 O GLU 90 12.461 9.383 41.245 1.00 39.73 A 664 N LYS 91 14.302 9.298 39.963 1.00 39.62 A 665 CA LYS 91 14.475 10.743 39.958 1.00 39.59 A 666 CB LYS 91 15.810 11.171 40.594 1.00 39.42 A 667 CG LYS 91 16.011 10.724 42.039 1.00 39.26 A 668 CD LYS 91 16.765 9.392 42.103 1.00 38.93 A 669 CE LYS 91 16.814 8.844 43.521 1.00 38.82 A 670 NZ LYS 91 17.615 7.592 43.607 1.00 38.74 A 671 C LYS 91 14.460 11.137 38.487 1.00 39.68 A 672 O LYS 91 14.992 10.425 37.641 1.00 39.50 A 673 N LEU 92 13.821 12.254 38.174 1.00 39.83 A 674 CA LEU 92 13.783 12.718 36.800 1.00 40.17 A 675 CB LEU 92 12.336 12.747 36.283 1.00 40.40 A 676 CG LEU 92 12.157 13.210 34.837 1.00 40.65 A 677 CD1 LEU 92 12.849 12.250 33.875 1.00 40.70 A 678 CD2 LEU 92 10.666 13.288 34.530 1.00 40.99 A 679 C LEU 92 14.390 14.119 36.785 1.00 40.17 A 680 O LEU 92 13.913 15.010 37.485 1.00 40.31 A 681 N ILE 93 15.463 14.301 36.022 1.00 40.18 A 682 CA ILE 93 16.112 15.600 35.945 1.00 40.24 A 683 CB ILE 93 17.638 15.520 36.226 1.00 40.35 A 684 CG2 ILE 93 18.256 16.909 36.135 1.00 40.08 A 685 CG1 ILE 93 17.904 14.954 37.623 1.00 40.48 A 686 CD1 ILE 93 17.779 13.466 37.716 1.00 40.93 A 687 C ILE 93 15.920 16.207 34.565 1.00 40.31 A 688 O ILE 93 16.262 15.596 33.549 1.00 40.16 A 689 N ARG 94 15.362 17.408 34.523 1.00 40.41 A 690 CA ARG 94 15.163 18.061 33.244 1.00 40.74 A 691 CB ARG 94 13.698 18.427 33.008 1.00 41.08 A 692 CG ARG 94 13.453 18.908 31.576 1.00 41.68 A 693 CD ARG 94 13.049 20.373 31.509 1.00 42.37 A 694 NE ARG 94 11.673 20.578 31.942 1.00 42.92 A 695 CZ ARG 94 11.073 21.762 32.013 1.00 43.32 A 696 NH1 ARG 94 11.724 22.867 31.680 1.00 43.61 A 697 NH2 ARG 94 9.814 21.844 32.423 1.00 43.78 A 698 C ARG 94 15.991 19.318 33.126 1.00 40.74 A 699 O ARG 94 15.840 20.255 33.913 1.00 40.65 A 700 N GLY 95 16.884 19.316 32.145 1.00 40.68 A 701 CA GLY 95 17.710 20.477 31.890 1.00 40.71 A 702 C GLY 95 17.156 21.129 30.639 1.00 40.71 A 703 O GLY 95 16.993 20.470 29.612 1.00 40.76 A 704 N SER 96 16.822 22.410 30.729 1.00 40.71 A 705 CA SER 96 16.301 23.142 29.582 1.00 40.80 A 706 CB SER 96 14.893 23.661 29.860 1.00 40.81 A 707 OG SER 96 13.985 22.583 29.977 1.00 40.67 A 708 C SER 96 17.244 24.306 29.336 1.00 40.89 A 709 O SER 96 17.483 25.122 30.230 1.00 40.93 A 710 N LYS 97 17.776 24.378 28.124 1.00 40.80 A 711 CA LYS 97 18.731 25.416 27.786 1.00 40.86 A 712 CB LYS 97 19.381 25.103 26.433 1.00 40.68 A 713 CG LYS 97 20.573 24.152 26.517 1.00 40.35 A 714 CD LYS 97 20.226 22.849 27.248 1.00 40.01 A 715 CE LYS 97 21.422 21.914 27.291 1.00 39.84 A 716 NZ LYS 97 21.064 20.548 27.771 1.00 39.74 A 717 C LYS 97 18.224 26.854 27.789 1.00 40.95 A 718 O LYS 97 17.078 27.145 27.423 1.00 40.98 A 719 N ILE 98 19.106 27.743 28.236 1.00 40.96 A 720 CA ILE 98 18.844 29.173 28.271 1.00 41.07 A 721 CB ILE 98 19.338 29.790 29.600 1.00 41.05 A 722 CG2 ILE 98 19.259 31.320 29.545 1.00 41.10 A 723 CG1 ILE 98 18.487 29.242 30.755 1.00 40.95 A 724 CD1 ILE 98 18.976 29.640 32.139 1.00 40.81 A 725 C ILE 98 19.650 29.702 27.089 1.00 41.19 A 726 O ILE 98 19.202 30.575 26.349 1.00 41.33 A 727 N ARG 99 20.847 29.154 26.919 1.00 41.28 A 728 CA ARG 99 21.717 29.509 25.807 1.00 41.49 A 729 CB ARG 99 23.057 30.052 26.305 1.00 41.83 A 730 CG ARG 99 22.983 31.464 26.849 1.00 42.32 A 731 CD ARG 99 24.379 31.981 27.150 1.00 42.87 A 732 NE ARG 99 24.403 33.442 27.207 1.00 43.34 A 733 CZ ARG 99 23.935 34.157 28.220 1.00 43.48 A 734 NH1 ARG 99 23.402 33.560 29.277 1.00 43.60 A 735 NH2 ARG 99 23.999 35.474 28.176 1.00 43.71 A 736 C ARG 99 21.948 28.230 25.004 1.00 41.43 A 737 O ARG 99 22.027 27.139 25.578 1.00 41.31 A 738 N GLU 100 22.070 28.370 23.687 1.00 41.29 A 739 CA GLU 100 22.257 27.220 22.814 1.00 41.18 A 740 CB GLU 100 22.101 27.635 21.339 1.00 41.57 A 741 CG GLU 100 22.404 26.510 20.338 1.00 42.34 A 742 CD GLU 100 21.843 26.775 18.940 1.00 42.90 A 743 OE1 GLU 100 22.205 26.045 17.987 1.00 43.25 A 744 OE2 GLU 100 21.026 27.707 18.790 1.00 43.46 A 745 C GLU 100 23.567 26.476 23.004 1.00 40.83 A 746 O GLU 100 24.650 27.054 22.948 1.00 40.71 A 747 N LEU 101 23.451 25.170 23.217 1.00 40.45 A 748 CA LEU 101 24.609 24.306 23.400 1.00 40.16 A 749 CB LEU 101 24.737 23.901 24.866 1.00 40.01 A 750 CG LEU 101 25.155 24.932 25.909 1.00 39.88 A 751 CD1 LEU 101 24.950 24.343 27.309 1.00 39.74 A 752 CD2 LEU 101 26.617 25.317 25.683 1.00 39.74 A 753 C LEU 101 24.440 23.043 22.564 1.00 40.00 A 754 O LEU 101 23.346 22.482 22.499 1.00 39.93 A 755 N SER 102 25.510 22.592 21.925 1.00 39.88 A 756 CA SER 102 25.426 21.370 21.145 1.00 39.84 A 757 CB SER 102 26.591 21.267 20.169 1.00 39.80 A 758 OG SER 102 27.791 20.981 20.859 1.00 39.80 A 759 C SER 102 25.511 20.231 22.158 1.00 39.87 A 760 O SER 102 25.879 20.451 23.317 1.00 39.66 A 761 N GLY 103 25.161 19.024 21.727 1.00 39.84 A 762 CA GLY 103 25.224 17.883 22.621 1.00 39.93 A 763 C GLY 103 26.632 17.705 23.161 1.00 40.16 A 764 O GLY 103 26.818 17.520 24.361 1.00 39.95 A 765 N PRO 104 27.652 17.743 22.288 1.00 40.42 A 766 CD PRO 104 27.560 17.647 20.819 1.00 40.48 A 767 CA PRO 104 29.041 17.584 22.731 1.00 40.70 A 768 CB PRO 104 29.826 17.659 21.424 1.00 40.56 A 769 CG PRO 104 28.893 17.020 20.452 1.00 40.54 A 770 C PRO 104 29.455 18.676 23.720 1.00 40.97 A 771 O PRO 104 30.128 18.399 24.714 1.00 40.96 A 772 N GLU 105 29.048 19.914 23.444 1.00 41.22 A 773 CA GLU 105 29.388 21.042 24.306 1.00 41.61 A 774 CB GLU 105 28.878 22.354 23.702 1.00 41.92 A 775 CG GLU 105 29.707 22.892 22.535 1.00 42.68 A 776 CD GLU 105 29.090 24.149 21.916 1.00 43.02 A 777 OE1 GLU 105 29.835 24.943 21.305 1.00 43.62 A 778 OE2 GLU 105 27.863 24.345 22.030 1.00 43.13 A 779 C GLU 105 28.794 20.870 25.698 1.00 41.62 A 780 O GLU 105 29.488 20.994 26.708 1.00 41.58 A 781 N TYR 106 27.497 20.600 25.742 1.00 41.60 A 782 CA TYR 106 26.804 20.411 27.001 1.00 41.79 A 783 CB TYR 106 25.310 20.229 26.750 1.00 41.53 A 784 CG TYR 106 24.564 19.746 27.967 1.00 41.25 A 785 CD1 TYR 106 24.233 20.623 29.000 1.00 41.04 A 786 CE1 TYR 106 23.595 20.167 30.155 1.00 40.92 A 787 CD2 TYR 106 24.237 18.396 28.114 1.00 41.14 A 788 CE2 TYR 106 23.602 17.932 29.261 1.00 40.81 A 789 CZ TYR 106 23.285 18.819 30.273 1.00 40.79 A 790 OH TYR 106 22.664 18.357 31.404 1.00 40.49 A 791 C TYR 106 27.332 19.202 27.768 1.00 42.09 A 792 O TYR 106 27.694 19.306 28.938 1.00 42.10 A 793 N SER 107 27.386 18.057 27.100 1.00 42.42 A 794 CA SER 107 27.829 16.823 27.737 1.00 42.92 A 795 CB SER 107 27.668 15.640 26.774 1.00 42.84 A 796 OG SER 107 28.508 15.765 25.645 1.00 42.92 A 797 C SER 107 29.257 16.878 28.254 1.00 43.18 A 798 O SER 107 29.586 16.220 29.242 1.00 42.97 A 799 N ARG 108 30.112 17.668 27.615 1.00 43.61 A 800 CA ARG 108 31.502 17.763 28.027 1.00 44.18 A 801 CB ARG 108 32.250 18.796 27.185 1.00 44.91 A 802 CG ARG 108 33.755 18.799 27.407 1.00 46.10 A 803 CD ARG 108 34.408 19.994 26.733 1.00 47.26 A 804 NE ARG 108 35.852 20.020 26.944 1.00 48.40 A 805 CZ ARG 108 36.722 19.304 26.240 1.00 49.05 A 806 NH1 ARG 108 36.292 18.501 25.275 1.00 49.36 A 807 NH2 ARG 108 38.019 19.390 26.501 1.00 49.37 A 808 C ARG 108 31.607 18.104 29.503 1.00 44.06 A 809 O ARG 108 32.292 17.405 30.263 1.00 44.00 A 810 N LYS 109 30.958 19.181 29.940 1.00 44.03 A 811 CA LYS 109 31.033 19.603 31.331 1.00 44.10 A 812 CB LYS 109 30.403 20.985 31.507 1.00 44.72 A 813 CG LYS 109 31.074 22.080 30.693 1.00 45.65 A 814 CD LYS 109 32.449 22.414 31.248 1.00 46.30 A 815 CE LYS 109 33.269 23.210 30.245 1.00 46.72 A 816 NZ LYS 109 34.617 23.551 30.776 1.00 47.36 A 817 C LYS 109 30.359 18.590 32.248 1.00 43.77 A 818 O LYS 109 30.894 18.272 33.314 1.00 43.65 A 819 N VAL 110 29.189 18.088 31.867 1.00 43.35 A 820 CA VAL 110 28.498 17.111 32.707 1.00 42.90 A 821 CB VAL 110 27.146 16.668 32.087 1.00 42.83 A 822 CG1 VAL 110 26.512 15.580 32.945 1.00 42.48 A 823 CG2 VAL 110 26.210 17.869 31.980 1.00 42.55 A 824 C VAL 110 29.373 15.884 32.921 1.00 42.75 A 825 O VAL 110 29.565 15.434 34.052 1.00 42.30 A 826 N MET 111 29.914 15.350 31.834 1.00 42.78 A 827 CA MET 111 30.765 14.176 31.919 1.00 42.98 A 828 CB MET 111 31.184 13.709 30.523 1.00 43.15 A 829 CG MET 111 30.008 13.332 29.614 1.00 43.57 A 830 SD MET 111 30.531 12.486 28.103 1.00 44.26 A 831 CE MET 111 31.374 13.836 27.227 1.00 44.12 A 832 C MET 111 32.003 14.449 32.770 1.00 43.03 A 833 O MET 111 32.434 13.585 33.533 1.00 43.04 A 834 N GLU 112 32.579 15.644 32.637 1.00 42.98 A 835 CA GLU 112 33.766 15.999 33.418 1.00 42.93 A 836 CB GLU 112 34.186 17.449 33.153 1.00 43.27 A 837 CG GLU 112 34.872 17.649 31.820 1.00 44.06 A 838 CD GLU 112 35.236 19.101 31.547 1.00 44.44 A 839 OE1 GLU 112 34.995 19.967 32.423 1.00 44.81 A 840 OE2 GLU 112 35.766 19.368 30.444 1.00 44.92 A 841 C GLU 112 33.473 15.834 34.897 1.00 42.51 A 842 O GLU 112 34.205 15.157 35.614 1.00 42.29 A 843 N ASN 113 32.392 16.466 35.339 1.00 42.25 A 844 CA ASN 113 31.976 16.403 36.732 1.00 42.06 A 845 CB ASN 113 30.792 17.336 36.953 1.00 42.02 A 846 CG ASN 113 31.160 18.778 36.713 1.00 42.12 A 847 OD1 ASN 113 32.324 19.080 36.443 1.00 41.97 A 848 ND2 ASN 113 30.184 19.677 36.810 1.00 41.88 A 849 C ASN 113 31.624 14.992 37.174 1.00 42.00 A 850 O ASN 113 31.921 14.598 38.309 1.00 41.99 A 851 N CYS 114 30.992 14.228 36.286 1.00 41.78 A 852 CA CYS 114 30.626 12.862 36.622 1.00 41.74 A 853 CB CYS 114 29.749 12.244 35.522 1.00 41.53 A 854 SG CYS 114 28.039 12.830 35.584 1.00 41.30 A 855 C CYS 114 31.884 12.037 36.815 1.00 41.88 A 856 O CYS 114 32.001 11.280 37.775 1.00 41.78 A 857 N VAL 115 32.836 12.196 35.907 1.00 42.06 A 858 CA VAL 115 34.075 11.447 35.999 1.00 42.47 A 859 CB VAL 115 34.954 11.695 34.757 1.00 42.46 A 860 CG1 VAL 115 36.291 10.987 34.909 1.00 42.38 A 861 CG2 VAL 115 34.226 11.195 33.514 1.00 42.49 A 862 C VAL 115 34.854 11.801 37.268 1.00 42.74 A 863 O VAL 115 35.393 10.920 37.933 1.00 42.62 A 864 N ALA 116 34.908 13.088 37.599 1.00 43.18 A 865 CA ALA 116 35.618 13.535 38.795 1.00 43.74 A 866 CB ALA 116 35.552 15.063 38.913 1.00 43.60 A 867 C ALA 116 34.972 12.883 40.015 1.00 44.09 A 868 O ALA 116 35.653 12.348 40.892 1.00 44.07 A 869 N HIS 117 33.648 12.929 40.071 1.00 44.53 A 870 CA HIS 117 32.950 12.315 41.189 1.00 44.95 A 871 CB HIS 117 31.433 12.446 41.032 1.00 45.11 A 872 CG HIS 117 30.664 11.576 41.979 1.00 45.31 A 873 CD2 HIS 117 29.919 10.467 41.762 1.00 45.38 A 874 ND1 HIS 117 30.687 11.763 43.346 1.00 45.33 A 875 CE1 HIS 117 29.992 10.803 43.929 1.00 45.43 A 876 NE2 HIS 117 29.516 10.002 42.991 1.00 45.53 A 877 C HIS 117 33.306 10.838 41.285 1.00 45.24 A 878 O HIS 117 33.764 10.369 42.323 1.00 45.23 A 879 N LEU 118 33.101 10.112 40.192 1.00 45.60 A 880 CA LEU 118 33.368 8.679 40.161 1.00 46.15 A 881 CB LEU 118 33.093 8.129 38.765 1.00 46.02 A 882 CG LEU 118 31.624 8.251 38.350 1.00 46.10 A 883 CD1 LEU 118 31.475 7.974 36.859 1.00 46.01 A 884 CD2 LEU 118 30.779 7.286 39.180 1.00 46.11 A 885 C LEU 118 34.774 8.306 40.610 1.00 46.58 A 886 O LEU 118 34.943 7.379 41.403 1.00 46.56 A 887 N LYS 119 35.779 9.010 40.097 1.00 47.09 A 888 CA LYS 119 37.159 8.740 40.492 1.00 47.62 A 889 CB LYS 119 38.133 9.573 39.655 1.00 47.78 A 890 CG LYS 119 38.212 9.155 38.205 1.00 48.15 A 891 CD LYS 119 39.222 9.999 37.451 1.00 48.55 A 892 CE LYS 119 39.383 9.510 36.029 1.00 48.80 A 893 NZ LYS 119 40.542 10.166 35.376 1.00 49.23 A 894 C LYS 119 37.296 9.109 41.966 1.00 47.88 A 895 O LYS 119 37.943 8.407 42.737 1.00 48.10 A 896 N SER 120 36.665 10.212 42.352 1.00 48.12 A 897 CA SER 120 36.700 10.680 43.731 1.00 48.39 A 898 CB SER 120 35.782 11.894 43.887 1.00 48.60 A 899 OG SER 120 35.518 12.166 45.253 1.00 49.22 A 900 C SER 120 36.283 9.603 44.731 1.00 48.39 A 901 O SER 120 36.952 9.388 45.745 1.00 48.52 A 902 N VAL 121 35.180 8.922 44.441 1.00 48.23 A 903 CA VAL 121 34.667 7.886 45.332 1.00 48.06 A 904 CB VAL 121 33.126 7.883 45.325 1.00 48.03 A 905 CG1 VAL 121 32.608 9.247 45.771 1.00 48.02 A 906 CG2 VAL 121 32.609 7.555 43.927 1.00 48.00 A 907 C VAL 121 35.172 6.483 45.000 1.00 47.91 A 908 O VAL 121 34.633 5.493 45.491 1.00 47.99 A 909 N GLY 122 36.200 6.403 44.163 1.00 47.73 A 910 CA GLY 122 36.774 5.116 43.804 1.00 47.44 A 911 C GLY 122 35.947 4.142 42.981 1.00 47.28 A 912 O GLY 122 36.156 2.935 43.070 1.00 47.24 A 913 N THR 123 35.012 4.641 42.178 1.00 47.14 A 914 CA THR 123 34.200 3.759 41.347 1.00 46.98 A 915 CB THR 123 32.724 3.717 41.805 1.00 46.91 A 916 OG1 THR 123 32.113 4.994 41.583 1.00 46.66 A 917 CG2 THR 123 32.639 3.353 43.281 1.00 46.84 A 918 C THR 123 34.238 4.205 39.890 1.00 46.97 A 919 O THR 123 33.216 4.571 39.306 1.00 46.92 A 920 N TYR 124 35.429 4.195 39.308 1.00 46.84 A 921 CA TYR 124 35.564 4.576 37.917 1.00 46.66 A 922 CB TYR 124 36.176 5.971 37.774 1.00 46.86 A 923 CG TYR 124 36.098 6.477 36.347 1.00 47.23 A 924 CD1 TYR 124 34.862 6.719 35.747 1.00 47.38 A 925 CE1 TYR 124 34.768 7.134 34.425 1.00 47.54 A 926 CD2 TYR 124 37.251 6.669 35.580 1.00 47.35 A 927 CE2 TYR 124 37.168 7.086 34.245 1.00 47.53 A 928 CZ TYR 124 35.923 7.315 33.679 1.00 47.66 A 929 OH TYR 124 35.823 7.719 32.368 1.00 47.86 A 930 C TYR 124 36.444 3.558 37.227 1.00 46.44 A 931 O TYR 124 37.627 3.798 36.999 1.00 46.53 A 932 N GLY 125 35.858 2.409 36.912 1.00 46.10 A 933 CA GLY 125 36.589 1.354 36.239 1.00 45.74 A 934 C GLY 125 36.263 1.351 34.761 1.00 45.52 A 935 O GLY 125 35.666 2.302 34.249 1.00 45.43 A 936 N ASP 126 36.648 .284 34.068 1.00 45.30 A 937 CA ASP 126 36.388 .191 32.643 1.00 45.09 A 938 CB ASP 126 36.925 −1.128 32.079 1.00 45.36 A 939 CG ASP 126 38.446 −1.241 32.192 1.00 45.63 A 940 OD1 ASP 126 39.137 −.197 32.225 1.00 45.67 A 941 OD2 ASP 126 38.950 −2.382 32.233 1.00 45.82 A 942 C ASP 126 34.897 .304 32.358 1.00 44.81 A 943 O ASP 126 34.483 1.018 31.444 1.00 44.67 A 944 N ALA 127 34.091 −.394 33.152 1.00 44.39 A 945 CA ALA 127 32.648 −.361 32.967 1.00 44.02 A 946 CB ALA 127 31.956 −1.222 34.028 1.00 43.92 A 947 C ALA 127 32.130 1.074 33.024 1.00 43.76 A 948 O ALA 127 31.348 1.487 32.166 1.00 43.61 A 949 N GLU 128 32.572 1.843 34.014 1.00 43.55 A 950 CA GLU 128 32.111 3.224 34.126 1.00 43.62 A 951 CB GLU 128 32.531 3.845 35.463 1.00 43.55 A 952 CG GLU 128 31.788 3.279 36.678 1.00 43.55 A 953 CD GLU 128 32.126 1.824 36.941 1.00 43.58 A 954 OE1 GLU 128 33.327 1.508 37.052 1.00 43.53 A 955 OE2 GLU 128 31.201 .991 37.042 1.00 43.62 A 956 C GLU 128 32.620 4.086 32.972 1.00 43.60 A 957 O GLU 128 31.911 4.971 32.500 1.00 43.55 A 958 N ALA 129 33.844 3.827 32.523 1.00 43.63 A 959 CA ALA 129 34.422 4.585 31.412 1.00 43.86 A 960 CB ALA 129 35.885 4.182 31.194 1.00 43.78 A 961 C ALA 129 33.606 4.302 30.159 1.00 43.88 A 962 O ALA 129 33.249 5.210 29.415 1.00 43.98 A 963 N GLU 130 33.305 3.032 29.930 1.00 44.01 A 964 CA GLU 130 32.517 2.656 28.774 1.00 44.23 A 965 CB GLU 130 32.422 1.135 28.683 1.00 44.93 A 966 CG GLU 130 33.741 .489 28.282 1.00 46.16 A 967 CD GLU 130 33.736 −1.016 28.465 1.00 47.06 A 968 OE1 GLU 130 32.695 −1.650 28.167 1.00 47.65 A 969 OE2 GLU 130 34.778 −1.569 28.896 1.00 47.67 A 970 C GLU 130 31.128 3.280 28.859 1.00 43.90 A 971 O GLU 130 30.576 3.718 27.849 1.00 43.72 A 972 N ALA 131 30.568 3.329 30.065 1.00 43.53 A 973 CA ALA 131 29.249 3.919 30.254 1.00 43.31 A 974 CB ALA 131 28.762 3.709 31.688 1.00 43.09 A 975 C ALA 131 29.308 5.407 29.931 1.00 43.19 A 976 O ALA 131 28.388 5.952 29.318 1.00 43.03 A 977 N MET 132 30.389 6.066 30.337 1.00 43.13 A 978 CA MET 132 30.530 7.492 30.060 1.00 43.23 A 979 CB MET 132 31.697 8.086 30.849 1.00 43.34 A 980 CG MET 132 31.472 8.107 32.353 1.00 43.56 A 981 SD MET 132 29.878 8.840 32.809 1.00 43.96 A 982 CE MET 132 30.021 10.478 32.064 1.00 43.50 A 983 C MET 132 30.721 7.754 28.565 1.00 43.26 A 984 O MET 132 30.315 8.802 28.058 1.00 43.15 A 985 N GLN 133 31.337 6.806 27.862 1.00 43.25 A 986 CA GLN 133 31.539 6.956 26.420 1.00 43.48 A 987 CB GLN 133 32.523 5.903 25.893 1.00 43.88 A 988 CG GLN 133 32.779 5.983 24.384 1.00 44.76 A 989 CD GLN 133 33.188 7.381 23.923 1.00 45.33 A 990 OE1 GLN 133 34.118 7.984 24.469 1.00 45.84 A 991 NE2 GLN 133 32.494 7.901 22.913 1.00 45.68 A 992 C GLN 133 30.180 6.794 25.748 1.00 43.22 A 993 O GLN 133 29.849 7.509 24.798 1.00 43.19 A 994 N LYS 134 29.383 5.859 26.257 1.00 42.89 A 995 CA LYS 134 28.054 5.646 25.704 1.00 42.64 A 996 CB LYS 134 27.389 4.436 26.360 1.00 42.74 A 997 CG LYS 134 26.011 4.115 25.805 1.00 42.92 A 998 CD LYS 134 25.502 2.779 26.345 1.00 43.17 A 999 CE LYS 134 24.109 2.464 25.830 1.00 43.26 A 1000 NZ LYS 134 23.665 1.122 26.298 1.00 43.66 A 1001 C LYS 134 27.250 6.912 25.985 1.00 42.33 A 1002 O LYS 134 26.435 7.349 25.173 1.00 42.13 A 1003 N PHE 135 27.496 7.499 27.149 1.00 42.17 A 1004 CA PHE 135 26.825 8.728 27.543 1.00 41.95 A 1005 CB PHE 135 27.363 9.173 28.905 1.00 41.89 A 1006 CG PHE 135 26.648 10.357 29.503 1.00 41.74 A 1007 CD1 PHE 135 25.641 10.173 30.439 1.00 41.59 A 1008 CD2 PHE 135 27.025 11.656 29.170 1.00 41.62 A 1009 CE1 PHE 135 25.021 11.265 31.047 1.00 41.62 A 1010 CE2 PHE 135 26.412 12.752 29.771 1.00 41.54 A 1011 CZ PHE 135 25.410 12.555 30.713 1.00 41.53 A 1012 C PHE 135 27.154 9.770 26.465 1.00 41.96 A 1013 O PHE 135 26.262 10.364 25.858 1.00 41.77 A 1014 N ALA 136 28.448 9.965 26.223 1.00 42.04 A 1015 CA ALA 136 28.922 10.931 25.229 1.00 42.27 A 1016 CB ALA 136 30.444 10.863 25.125 1.00 42.09 A 1017 C ALA 136 28.307 10.689 23.858 1.00 42.41 A 1018 O ALA 136 27.848 11.618 23.193 1.00 42.42 A 1019 N GLU 137 28.303 9.430 23.440 1.00 42.64 A 1020 CA GLU 137 27.767 9.061 22.141 1.00 43.03 A 1021 CB GLU 137 27.875 7.550 21.951 1.00 43.75 A 1022 CG GLU 137 28.505 7.155 20.644 1.00 45.13 A 1023 CD GLU 137 29.983 7.466 20.611 1.00 45.82 A 1024 OE1 GLU 137 30.723 6.842 21.406 1.00 46.56 A 1025 OE2 GLU 137 30.400 8.329 19.801 1.00 46.16 A 1026 C GLU 137 26.317 9.488 21.970 1.00 42.71 A 1027 O GLU 137 25.917 9.950 20.899 1.00 42.80 A 1028 N ALA 138 25.527 9.332 23.025 1.00 42.31 A 1029 CA ALA 138 24.116 9.691 22.962 1.00 41.96 A 1030 CB ALA 138 23.417 9.279 24.254 1.00 41.98 A 1031 C ALA 138 23.894 11.181 22.707 1.00 41.72 A 1032 O ALA 138 22.880 11.571 22.128 1.00 41.54 A 1033 N PHE 139 24.837 12.012 23.140 1.00 41.34 A 1034 CA PHE 139 24.700 13.455 22.965 1.00 41.15 A 1035 CB PHE 139 25.381 14.213 24.111 1.00 40.74 A 1036 CG PHE 139 24.588 14.245 25.387 1.00 40.50 A 1037 CD1 PHE 139 24.687 13.214 26.315 1.00 40.18 A 1038 CD2 PHE 139 23.760 15.329 25.672 1.00 40.30 A 1039 CE1 PHE 139 23.978 13.264 27.512 1.00 40.10 A 1040 CE2 PHE 139 23.042 15.388 26.872 1.00 40.16 A 1041 CZ PHE 139 23.154 14.354 27.791 1.00 40.04 A 1042 C PHE 139 25.240 14.010 21.655 1.00 41.14 A 1043 O PHE 139 24.835 15.085 21.238 1.00 41.08 A 1044 N LYS 140 26.148 13.289 21.006 1.00 41.32 A 1045 CA LYS 140 26.745 13.779 19.764 1.00 41.72 A 1046 CB LYS 140 27.740 12.752 19.212 1.00 41.92 A 1047 CG LYS 140 28.978 12.587 20.086 1.00 42.34 A 1048 CD LYS 140 29.990 11.644 19.460 1.00 42.79 A 1049 CE LYS 140 31.231 11.518 20.342 1.00 43.20 A 1050 NZ LYS 140 32.244 10.587 19.749 1.00 43.64 A 1051 C LYS 140 25.807 14.230 18.641 1.00 41.79 A 1052 O LYS 140 26.063 15.245 17.992 1.00 41.89 A 1053 N PRO 141 24.714 13.494 18.393 1.00 41.82 A 1054 CD PRO 141 24.354 12.156 18.903 1.00 41.97 A 1055 CA PRO 141 23.803 13.904 17.318 1.00 41.80 A 1056 CB PRO 141 23.155 12.585 16.913 1.00 41.90 A 1057 CG PRO 141 23.005 11.898 18.229 1.00 41.95 A 1058 C PRO 141 22.765 14.931 17.748 1.00 41.71 A 1059 O PRO 141 21.848 15.254 16.995 1.00 41.61 A 1060 N VAL 142 22.915 15.456 18.955 1.00 41.56 A 1061 CA VAL 142 21.938 16.397 19.466 1.00 41.56 A 1062 CB VAL 142 21.417 15.924 20.850 1.00 41.66 A 1063 CG1 VAL 142 20.292 16.833 21.335 1.00 41.67 A 1064 CG2 VAL 142 20.936 14.473 20.755 1.00 41.81 A 1065 C VAL 142 22.427 17.832 19.606 1.00 41.50 A 1066 O VAL 142 23.612 18.089 19.826 1.00 41.47 A 1067 N ASN 143 21.496 18.762 19.447 1.00 41.33 A 1068 CA ASN 143 21.794 20.168 19.626 1.00 41.38 A 1069 CB ASN 143 21.789 20.935 18.302 1.00 41.38 A 1070 CG ASN 143 22.159 22.406 18.491 1.00 41.39 A 1071 OD1 ASN 143 23.181 22.719 19.103 1.00 41.27 A 1072 ND2 ASN 143 21.330 23.306 17.972 1.00 41.22 A 1073 C ASN 143 20.704 20.702 20.533 1.00 41.38 A 1074 O ASN 143 19.545 20.281 20.442 1.00 41.22 A 1075 N PHE 144 21.070 21.615 21.422 1.00 41.46 A 1076 CA PHE 144 20.097 22.179 22.342 1.00 41.70 A 1077 CB PHE 144 20.501 21.926 23.801 1.00 41.45 A 1078 CG PHE 144 20.604 20.471 24.174 1.00 41.40 A 1079 CD1 PHE 144 21.843 19.843 24.239 1.00 41.20 A 1080 CD2 PHE 144 19.458 19.739 24.498 1.00 41.26 A 1081 CE1 PHE 144 21.952 18.504 24.625 1.00 41.32 A 1082 CE2 PHE 144 19.550 18.398 24.884 1.00 41.35 A 1083 CZ PHE 144 20.798 17.779 24.949 1.00 41.26 A 1084 C PHE 144 19.880 23.677 22.174 1.00 41.98 A 1085 O PHE 144 20.526 24.486 22.847 1.00 41.96 A 1086 N PRO 145 18.991 24.073 21.255 1.00 42.28 A 1087 CD PRO 145 18.284 23.323 20.200 1.00 42.24 A 1088 CA PRO 145 18.770 25.512 21.117 1.00 42.29 A 1089 CB PRO 145 17.942 25.611 19.836 1.00 42.43 A 1090 CG PRO 145 17.196 24.295 19.807 1.00 42.47 A 1091 C PRO 145 17.990 25.933 22.367 1.00 42.41 A 1092 O PRO 145 17.510 25.075 23.124 1.00 42.42 A 1093 N PRO 146 17.863 27.247 22.616 1.00 42.40 A 1094 CD PRO 146 18.349 28.400 21.833 1.00 42.37 A 1095 CA PRO 146 17.126 27.687 23.802 1.00 42.32 A 1096 CB PRO 146 16.937 29.180 23.554 1.00 42.35 A 1097 CG PRO 146 18.196 29.542 22.812 1.00 42.35 A 1098 C PRO 146 15.795 26.957 23.938 1.00 42.26 A 1099 O PRO 146 15.071 26.794 22.963 1.00 42.31 A 1100 N GLY 147 15.476 26.517 25.148 1.00 42.22 A 1101 CA GLY 147 14.221 25.819 25.360 1.00 42.03 A 1102 C GLY 147 14.317 24.318 25.147 1.00 41.85 A 1103 O GLY 147 13.484 23.572 25.668 1.00 41.83 A 1104 N ALA 148 15.312 23.879 24.375 1.00 41.67 A 1105 CA ALA 148 15.515 22.452 24.116 1.00 41.47 A 1106 CB ALA 148 16.627 22.240 23.091 1.00 41.48 A 1107 C ALA 148 15.889 21.814 25.446 1.00 41.43 A 1108 O ALA 148 16.473 22.472 26.317 1.00 41.33 A 1109 N SER 149 15.571 20.533 25.608 1.00 41.17 A 1110 CA SER 149 15.833 19.884 26.881 1.00 40.92 A 1111 CB SER 149 14.532 19.772 27.668 1.00 40.88 A 1112 OG SER 149 13.888 21.022 27.774 1.00 41.22 A 1113 C SER 149 16.467 18.513 26.856 1.00 40.65 A 1114 O SER 149 16.417 17.788 25.860 1.00 40.68 A 1115 N VAL 150 17.069 18.171 27.986 1.00 40.32 A 1116 CA VAL 150 17.665 16.865 28.172 1.00 39.84 A 1117 CB VAL 150 19.185 16.939 28.436 1.00 39.89 A 1118 CG1 VAL 150 19.479 17.829 29.651 1.00 39.70 A 1119 CG2 VAL 150 19.724 15.533 28.670 1.00 39.82 A 1120 C VAL 150 16.960 16.328 29.404 1.00 39.59 A 1121 O VAL 150 16.746 17.058 30.374 1.00 39.45 A 1122 N PHE 151 16.560 15.063 29.351 1.00 39.30 A 1123 CA PHE 151 15.891 14.440 30.480 1.00 38.87 A 1124 CB PHE 151 14.508 13.928 30.077 1.00 39.13 A 1125 CG PHE 151 13.509 15.015 29.823 1.00 39.25 A 1126 CD1 PHE 151 12.636 15.420 30.826 1.00 39.37 A 1127 CD2 PHE 151 13.438 15.632 28.578 1.00 39.36 A 1128 CE1 PHE 151 11.699 16.425 30.597 1.00 39.52 A 1129 CE2 PHE 151 12.503 16.641 28.336 1.00 39.54 A 1130 CZ PHE 151 11.634 17.037 29.345 1.00 39.45 A 1131 C PHE 151 16.724 13.270 30.973 1.00 38.58 A 1132 O PHE 151 17.062 12.366 30.205 1.00 38.41 A 1133 N TYR 152 17.076 13.308 32.252 1.00 38.13 A 1134 CA TYR 152 17.834 12.227 32.857 1.00 37.88 A 1135 CB TYR 152 18.949 12.746 33.768 1.00 37.88 A 1136 CG TYR 152 20.021 13.550 33.079 1.00 37.74 A 1137 CD1 TYR 152 19.977 14.945 33.066 1.00 37.66 A 1138 CE1 TYR 152 20.986 15.689 32.447 1.00 37.66 A 1139 CD2 TYR 152 21.092 12.917 32.459 1.00 37.76 A 1140 CE2 TYR 152 22.101 13.644 31.841 1.00 37.59 A 1141 CZ TYR 152 22.043 15.029 31.841 1.00 37.66 A 1142 OH TYR 152 23.056 15.750 31.251 1.00 37.80 A 1143 C TYR 152 16.857 11.465 33.729 1.00 37.79 A 1144 O TYR 152 16.323 12.020 34.695 1.00 37.55 A 1145 N ARG 153 16.597 10.210 33.387 1.00 37.54 A 1146 CA ARG 153 15.711 9.416 34.221 1.00 37.53 A 1147 CB ARG 153 14.763 8.555 33.384 1.00 37.44 A 1148 CG ARG 153 13.813 7.728 34.245 1.00 37.32 A 1149 CD ARG 153 12.827 6.961 33.373 1.00 37.28 A 1150 NE ARG 153 13.515 6.054 32.462 1.00 37.30 A 1151 CZ ARG 153 13.946 4.839 32.786 1.00 37.33 A 1152 NH1 ARG 153 13.758 4.361 34.013 1.00 37.43 A 1153 NH2 ARG 153 14.574 4.107 31.878 1.00 37.25 A 1154 C ARG 153 16.626 8.519 35.030 1.00 37.57 A 1155 O ARG 153 17.244 7.603 34.487 1.00 37.45 A 1156 N GLN 154 16.741 8.798 36.321 1.00 37.63 A 1157 CA GLN 154 17.597 7.988 37.173 1.00 37.90 A 1158 CB GLN 154 18.270 8.850 38.247 1.00 37.95 A 1159 CG GLN 154 19.330 8.096 39.051 1.00 38.05 A 1160 CD GLN 154 19.810 8.881 40.260 1.00 38.19 A 1161 OE1 GLN 154 19.877 10.110 40.226 1.00 38.28 A 1162 NE2 GLN 154 20.153 8.175 41.330 1.00 38.08 A 1163 C GLN 154 16.766 6.901 37.841 1.00 38.01 A 1164 O GLN 154 16.024 7.159 38.790 1.00 37.91 A 1165 N SER 155 16.886 5.688 37.320 1.00 38.27 A 1166 CA SER 155 16.167 4.545 37.852 1.00 38.62 A 1167 CB SER 155 16.046 3.470 36.784 1.00 38.57 A 1168 OG SER 155 15.731 2.229 37.378 1.00 39.38 A 1169 C SER 155 16.936 3.993 39.042 1.00 38.76 A 1170 O SER 155 18.162 3.876 39.000 1.00 38.81 A 1171 N PRO 156 16.227 3.633 40.120 1.00 38.88 A 1172 CD PRO 156 14.770 3.655 40.339 1.00 38.95 A 1173 CA PRO 156 16.928 3.098 41.288 1.00 38.90 A 1174 CB PRO 156 15.835 3.050 42.349 1.00 38.90 A 1175 CG PRO 156 14.612 2.752 41.539 1.00 38.97 A 1176 C PRO 156 17.544 1.734 40.996 1.00 38.81 A 1177 O PRO 156 18.340 1.219 41.782 1.00 38.90 A 1178 N ASP 157 17.180 1.160 39.854 1.00 38.77 A 1179 CA ASP 157 17.699 −.144 39.457 1.00 38.75 A 1180 CB ASP 157 16.699 −.854 38.538 1.00 39.02 A 1181 CG ASP 157 15.319 −.949 39.150 1.00 39.26 A 1182 OD1 ASP 157 15.225 −1.296 40.345 1.00 39.28 A 1183 OD2 ASP 157 14.326 −.680 38.436 1.00 39.64 A 1184 C ASP 157 19.065 −.048 38.764 1.00 38.67 A 1185 O ASP 157 19.506 −.991 38.111 1.00 38.65 A 1186 N GLY 158 19.721 1.102 38.893 1.00 38.54 A 1187 CA GLY 158 21.042 1.269 38.312 1.00 38.54 A 1188 C GLY 158 21.105 1.553 36.826 1.00 38.44 A 1189 O GLY 158 22.040 1.132 36.143 1.00 38.40 A 1190 N ILE 159 20.115 2.275 36.321 1.00 38.42 A 1191 CA ILE 159 20.074 2.619 34.909 1.00 38.43 A 1192 CB ILE 159 18.963 1.846 34.159 1.00 38.57 A 1193 CG2 ILE 159 18.839 2.368 32.726 1.00 38.58 A 1194 CG1 ILE 159 19.270 .346 34.174 1.00 38.75 A 1195 CD1 ILE 159 18.225 −.505 33.457 1.00 39.00 A 1196 C ILE 159 19.786 4.099 34.784 1.00 38.38 A 1197 O ILE 159 19.019 4.663 35.565 1.00 38.19 A 1198 N LEU 160 20.426 4.731 33.812 1.00 38.40 A 1199 CA LEU 160 20.214 6.148 33.582 1.00 38.59 A 1200 CB LEU 160 21.539 6.910 33.673 1.00 38.58 A 1201 CG LEU 160 21.456 8.411 33.380 1.00 38.62 A 1202 CD1 LEU 160 20.672 9.103 34.482 1.00 38.51 A 1203 CD2 LEU 160 22.867 8.990 33.278 1.00 38.65 A 1204 C LEU 160 19.633 6.275 32.185 1.00 38.66 A 1205 O LEU 160 20.296 5.950 31.204 1.00 38.58 A 1206 N GLY 161 18.384 6.714 32.100 1.00 38.88 A 1207 CA GLY 161 17.765 6.872 30.799 1.00 39.27 A 1208 C GLY 161 17.975 8.281 30.278 1.00 39.47 A 1209 O GLY 161 17.758 9.249 31.004 1.00 39.35 A 1210 N LEU 162 18.407 8.393 29.027 1.00 39.76 A 1211 CA LEU 162 18.636 9.694 28.406 1.00 40.16 A 1212 CB LEU 162 20.042 9.757 27.805 1.00 40.00 A 1213 CG LEU 162 21.192 9.511 28.786 1.00 39.96 A 1214 CD1 LEU 162 22.527 9.575 28.044 1.00 39.90 A 1215 CD2 LEU 162 21.135 10.546 29.900 1.00 39.77 A 1216 C LEU 162 17.618 10.018 27.315 1.00 40.55 A 1217 O LEU 162 17.444 9.253 26.368 1.00 40.35 A 1218 N SER 163 16.958 11.160 27.464 1.00 41.13 A 1219 CA SER 163 15.974 11.631 26.497 1.00 41.76 A 1220 CB SER 163 14.566 11.585 27.086 1.00 41.76 A 1221 OG SER 163 14.176 10.256 27.345 1.00 42.44 A 1222 C SER 163 16.298 13.067 26.097 1.00 42.06 A 1223 O SER 163 16.758 13.863 26.917 1.00 41.82 A 1224 N PHE 164 16.049 13.386 24.834 1.00 42.54 A 1225 CA PHE 164 16.306 14.720 24.304 1.00 43.18 A 1226 CB PHE 164 17.444 14.662 23.294 1.00 43.12 A 1227 CG PHE 164 18.655 13.945 23.800 1.00 43.17 A 1228 CD1 PHE 164 19.087 12.771 23.194 1.00 43.26 A 1229 CD2 PHE 164 19.362 14.436 24.896 1.00 43.19 A 1230 CE1 PHE 164 20.209 12.095 23.672 1.00 43.22 A 1231 CE2 PHE 164 20.482 13.771 25.383 1.00 43.14 A 1232 CZ PHE 164 20.908 12.601 24.772 1.00 43.37 A 1233 C PHE 164 15.049 15.255 23.639 1.00 43.78 A 1234 O PHE 164 14.379 14.540 22.893 1.00 43.65 A 1235 N SER 165 14.731 16.513 23.919 1.00 44.59 A 1236 CA SER 165 13.551 17.150 23.355 1.00 45.52 A 1237 CB SER 165 12.523 17.403 24.458 1.00 45.60 A 1238 OG SER 165 11.409 18.123 23.962 1.00 45.95 A 1239 C SER 165 13.912 18.470 22.678 1.00 46.18 A 1240 O SER 165 14.866 19.143 23.081 1.00 46.10 A 1241 N PRO 166 13.160 18.849 21.625 1.00 46.85 A 1242 CD PRO 166 12.093 18.064 20.982 1.00 46.97 A 1243 CA PRO 166 13.396 20.098 20.890 1.00 47.32 A 1244 CB PRO 166 12.488 19.971 19.664 1.00 47.26 A 1245 CG PRO 166 12.218 18.495 19.556 1.00 47.29 A 1246 C PRO 166 12.965 21.264 21.766 1.00 47.81 A 1247 O PRO 166 13.396 22.400 21.573 1.00 47.92 A 1248 N ASP 167 12.083 20.964 22.714 1.00 48.36 A 1249 CA ASP 167 11.566 21.955 23.643 1.00 48.95 A 1250 CB ASP 167 10.156 22.381 23.236 1.00 49.26 A 1251 CG ASP 167 9.263 21.204 22.919 1.00 49.70 A 1252 OD1 ASP 167 9.256 20.227 23.704 1.00 49.86 A 1253 OD2 ASP 167 8.562 21.260 21.882 1.00 49.98 A 1254 C ASP 167 11.549 21.378 25.052 1.00 49.23 A 1255 O ASP 167 12.371 20.520 25.381 1.00 49.23 A 1256 N THR 168 10.608 21.825 25.878 1.00 49.60 A 1257 CA THR 168 10.537 21.366 27.259 1.00 50.10 A 1258 CB THR 168 10.070 22.504 28.192 1.00 50.15 A 1259 OG1 THR 168 8.771 22.947 27.781 1.00 50.34 A 1260 CG2 THR 168 11.047 23.678 28.142 1.00 50.15 A 1261 C THR 168 9.632 20.159 27.496 1.00 50.41 A 1262 O THR 168 9.537 19.672 28.621 1.00 50.48 A 1263 N SER 169 8.970 19.673 26.452 1.00 50.70 A 1264 CA SER 169 8.081 18.529 26.619 1.00 51.03 A 1265 CB SER 169 7.083 18.458 25.461 1.00 51.11 A 1266 OG SER 169 7.740 18.288 24.216 1.00 51.50 A 1267 C SER 169 8.888 17.234 26.707 1.00 51.10 A 1268 O SER 169 9.896 17.081 26.013 1.00 51.14 A 1269 N ILE 170 8.453 16.301 27.551 1.00 51.18 A 1270 CA ILE 170 9.126 15.021 27.726 1.00 51.37 A 1271 CB ILE 170 8.594 14.235 28.915 1.00 51.51 A 1272 CG2 ILE 170 9.475 13.025 29.174 1.00 51.59 A 1273 CG1 ILE 170 8.538 15.144 30.150 1.00 51.79 A 1274 CD1 ILE 170 7.897 14.447 31.361 1.00 52.03 A 1275 C ILE 170 8.967 14.132 26.527 1.00 51.28 A 1276 O ILE 170 7.856 13.844 26.074 1.00 51.32 A 1277 N PRO 171 10.076 13.654 25.972 1.00 51.20 A 1278 CD PRO 171 11.504 13.961 26.221 1.00 51.19 A 1279 CA PRO 171 9.868 12.800 24.800 1.00 51.10 A 1280 CB PRO 171 11.266 12.621 24.192 1.00 51.16 A 1281 CG PRO 171 12.262 13.161 25.172 1.00 51.18 A 1282 C PRO 171 9.230 11.482 25.188 1.00 51.04 A 1283 O PRO 171 9.411 11.000 26.316 1.00 50.87 A 1284 N GLU 172 8.491 10.897 24.253 1.00 50.95 A 1285 CA GLU 172 7.807 9.624 24.481 1.00 50.86 A 1286 CB GLU 172 6.855 9.351 23.309 1.00 51.49 A 1287 CG GLU 172 5.612 10.220 23.369 1.00 52.62 A 1288 CD GLU 172 4.708 9.847 24.542 1.00 53.33 A 1289 OE1 GLU 172 4.950 8.791 25.189 1.00 53.96 A 1290 OE2 GLU 172 3.737 10.599 24.818 1.00 53.74 A 1291 C GLU 172 8.801 8.469 24.653 1.00 50.31 A 1292 O GLU 172 8.588 7.577 25.471 1.00 50.24 A 1293 N LYS 173 9.895 8.512 23.897 1.00 49.72 A 1294 CA LYS 173 10.902 7.457 23.987 1.00 49.12 A 1295 CB LYS 173 11.030 6.736 22.644 1.00 49.50 A 1296 CG LYS 173 9.745 6.060 22.171 1.00 50.05 A 1297 CD LYS 173 10.013 5.108 20.993 1.00 50.55 A 1298 CE LYS 173 8.762 4.310 20.583 1.00 50.91 A 1299 NZ LYS 173 9.021 3.315 19.486 1.00 51.32 A 1300 C LYS 173 12.270 7.989 24.405 1.00 48.50 A 1301 O LYS 173 12.581 9.157 24.174 1.00 48.43 A 1302 N GLU 174 13.092 7.130 25.003 1.00 47.59 A 1303 CA GLU 174 14.421 7.554 25.418 1.00 46.78 A 1304 CB GLU 174 14.842 6.858 26.714 1.00 46.63 A 1305 CG GLU 174 13.877 7.093 27.860 1.00 46.41 A 1306 CD GLU 174 14.385 6.543 29.171 1.00 46.39 A 1307 OE1 GLU 174 14.706 5.330 29.226 1.00 46.38 A 1308 OE2 GLU 174 14.457 7.319 30.151 1.00 46.26 A 1309 C GLU 174 15.416 7.264 24.315 1.00 46.31 A 1310 O GLU 174 15.264 6.300 23.565 1.00 46.29 A 1311 N ALA 175 16.426 8.119 24.208 1.00 45.59 A 1312 CA ALA 175 17.449 7.971 23.185 1.00 44.97 A 1313 CB ALA 175 18.133 9.315 22.939 1.00 44.96 A 1314 C ALA 175 18.488 6.912 23.553 1.00 44.55 A 1315 O ALA 175 19.097 6.301 22.679 1.00 44.28 A 1316 N ALA 176 18.701 6.701 24.847 1.00 44.10 A 1317 CA ALA 176 19.678 5.707 25.279 1.00 43.81 A 1318 CB ALA 176 21.095 6.236 25.069 1.00 43.77 A 1319 C ALA 176 19.485 5.310 26.729 1.00 43.51 A 1320 O ALA 176 18.808 6.002 27.492 1.00 43.44 A 1321 N LEU 177 20.077 4.177 27.093 1.00 43.22 A 1322 CA LEU 177 20.012 3.657 28.452 1.00 42.98 A 1323 CB LEU 177 19.184 2.366 28.509 1.00 43.12 A 1324 CG LEU 177 17.671 2.444 28.282 1.00 43.23 A 1325 CD1 LEU 177 17.081 1.029 28.344 1.00 43.35 A 1326 CD2 LEU 177 17.026 3.324 29.344 1.00 43.13 A 1327 C LEU 177 21.428 3.354 28.897 1.00 42.67 A 1328 O LEU 177 22.101 2.514 28.305 1.00 42.82 A 1329 N ILE 178 21.891 4.046 29.928 1.00 42.22 A 1330 CA ILE 178 23.233 3.810 30.430 1.00 41.67 A 1331 CB ILE 178 23.907 5.121 30.894 1.00 41.77 A 1332 CG2 ILE 178 25.384 4.874 31.188 1.00 41.56 A 1333 CG1 ILE 178 23.762 6.197 29.812 1.00 41.63 A 1334 CD1 ILE 178 24.386 5.833 28.476 1.00 41.74 A 1335 C ILE 178 23.042 2.879 31.614 1.00 41.43 A 1336 O ILE 178 22.576 3.287 32.683 1.00 41.40 A 1337 N GLU 179 23.388 1.618 31.411 1.00 40.99 A 1338 CA GLU 179 23.225 .616 32.448 1.00 40.66 A 1339 CB GLU 179 22.782 −.695 31.801 1.00 41.14 A 1340 CG GLU 179 21.535 −.493 30.947 1.00 42.12 A 1341 CD GLU 179 20.907 −1.784 30.475 1.00 42.79 A 1342 OE1 GLU 179 19.833 −1.715 29.832 1.00 43.53 A 1343 OE2 GLU 179 21.475 −2.865 30.742 1.00 43.30 A 1344 C GLU 179 24.496 .440 33.263 1.00 40.04 A 1345 O GLU 179 25.349 −.388 32.951 1.00 39.95 A 1346 N ASN 180 24.609 1.251 34.306 1.00 39.27 A 1347 CA ASN 180 25.758 1.226 35.205 1.00 38.73 A 1348 CB ASN 180 26.945 1.954 34.566 1.00 38.45 A 1349 CG ASN 180 28.172 1.941 35.451 1.00 38.27 A 1350 OD1 ASN 180 28.282 2.728 36.390 1.00 38.08 A 1351 ND2 ASN 180 29.094 1.030 35.167 1.00 38.09 A 1352 C ASN 180 25.322 1.920 36.493 1.00 38.31 A 1353 O ASN 180 24.881 3.071 36.467 1.00 38.24 A 1354 N LYS 181 25.434 1.218 37.614 1.00 37.95 A 1355 CA LYS 181 24.994 1.760 38.900 1.00 37.61 A 1356 CB LYS 181 25.182 .718 40.012 1.00 37.74 A 1357 CG LYS 181 24.609 1.126 41.380 1.00 37.69 A 1358 CD LYS 181 23.125 1.471 41.280 1.00 37.99 A 1359 CE LYS 181 22.459 1.584 42.654 1.00 38.20 A 1360 NZ LYS 181 20.974 1.744 42.544 1.00 38.41 A 1361 C LYS 181 25.670 3.062 39.309 1.00 37.43 A 1362 O LYS 181 24.995 4.061 39.588 1.00 37.26 A 1363 N ALA 182 26.998 3.053 39.341 1.00 37.18 A 1364 CA ALA 182 27.757 4.231 39.747 1.00 37.12 A 1365 CB ALA 182 29.259 3.938 39.679 1.00 37.14 A 1366 C ALA 182 27.415 5.430 38.885 1.00 36.99 A 1367 O ALA 182 27.093 6.504 39.394 1.00 37.05 A 1368 N VAL 183 27.468 5.238 37.574 1.00 36.87 A 1369 CA VAL 183 27.173 6.319 36.653 1.00 36.72 A 1370 CB VAL 183 27.500 5.896 35.200 1.00 36.81 A 1371 CG1 VAL 183 27.086 6.986 34.212 1.00 36.71 A 1372 CG2 VAL 183 28.997 5.613 35.082 1.00 36.81 A 1373 C VAL 183 25.723 6.773 36.749 1.00 36.58 A 1374 O VAL 183 25.438 7.970 36.636 1.00 36.33 A 1375 N SER 184 24.808 5.836 37.001 1.00 36.47 A 1376 CA SER 184 23.394 6.199 37.057 1.00 36.55 A 1377 CB SER 184 22.513 4.974 37.364 1.00 36.41 A 1378 OG SER 184 22.561 4.611 38.731 1.00 36.53 A 1379 C SER 184 23.087 7.326 38.036 1.00 36.59 A 1380 O SER 184 22.214 8.149 37.767 1.00 36.57 A 1381 N SER 185 23.794 7.382 39.163 1.00 36.79 A 1382 CA SER 185 23.545 8.446 40.133 1.00 37.20 A 1383 CB SER 185 23.538 7.891 41.565 1.00 37.17 A 1384 OG SER 185 24.832 7.467 41.965 1.00 37.40 A 1385 C SER 185 24.549 9.603 40.047 1.00 37.45 A 1386 O SER 185 24.365 10.633 40.696 1.00 37.51 A 1387 N ALA 186 25.589 9.440 39.234 1.00 37.65 A 1388 CA ALA 186 26.622 10.469 39.097 1.00 37.89 A 1389 CB ALA 186 27.687 10.009 38.106 1.00 37.74 A 1390 C ALA 186 26.083 11.833 38.681 1.00 37.97 A 1391 O ALA 186 26.485 12.861 39.229 1.00 38.04 A 1392 N VAL 187 25.171 11.850 37.717 1.00 38.08 A 1393 CA VAL 187 24.621 13.111 37.252 1.00 38.22 A 1394 CB VAL 187 23.591 12.892 36.118 1.00 38.21 A 1395 CG1 VAL 187 23.066 14.230 35.629 1.00 38.05 A 1396 CG2 VAL 187 24.235 12.126 34.973 1.00 37.92 A 1397 C VAL 187 23.965 13.884 38.385 1.00 38.42 A 1398 O VAL 187 24.307 15.040 38.632 1.00 38.34 A 1399 N LEU 188 23.030 13.248 39.086 1.00 38.62 A 1400 CA LEU 188 22.339 13.916 40.181 1.00 38.82 A 1401 CB LEU 188 21.223 13.024 40.739 1.00 38.68 A 1402 CG LEU 188 20.362 13.651 41.840 1.00 38.63 A 1403 CD1 LEU 188 19.699 14.929 41.332 1.00 38.43 A 1404 CD2 LEU 188 19.311 12.642 42.285 1.00 38.52 A 1405 C LEU 188 23.320 14.288 41.293 1.00 39.05 A 1406 O LEU 188 23.174 15.321 41.936 1.00 39.02 A 1407 N GLU 189 24.316 13.439 41.512 1.00 39.35 A 1408 CA GLU 189 25.335 13.690 42.524 1.00 39.94 A 1409 CB GLU 189 26.382 12.573 42.487 1.00 40.24 A 1410 CG GLU 189 27.439 12.639 43.569 1.00 41.00 A 1411 CD GLU 189 26.921 12.218 44.942 1.00 41.45 A 1412 OE1 GLU 189 26.265 11.155 45.041 1.00 41.52 A 1413 OE2 GLU 189 27.185 12.943 45.927 1.00 41.70 A 1414 C GLU 189 26.021 15.041 42.271 1.00 40.13 A 1415 O GLU 189 26.260 15.808 43.204 1.00 39.98 A 1416 N THR 190 26.320 15.335 41.006 1.00 40.31 A 1417 CA THR 190 26.992 16.582 40.661 1.00 40.75 A 1418 CB THR 190 27.578 16.539 39.233 1.00 40.62 A 1419 OG1 THR 190 26.515 16.440 38.276 1.00 40.54 A 1420 CG2 THR 190 28.510 15.345 39.077 1.00 40.51 A 1421 C THR 190 26.053 17.775 40.761 1.00 41.14 A 1422 O THR 190 26.474 18.917 40.617 1.00 41.18 A 1423 N MET 191 24.780 17.511 41.016 1.00 41.50 A 1424 CA MET 191 23.812 18.591 41.125 1.00 42.08 A 1425 CB MET 191 22.542 18.231 40.356 1.00 42.19 A 1426 CG MET 191 22.790 17.885 38.900 1.00 42.52 A 1427 SD MET 191 21.284 17.304 38.120 1.00 42.98 A 1428 CE MET 191 21.674 17.510 36.378 1.00 43.11 A 1429 C MET 191 23.460 18.926 42.573 1.00 42.40 A 1430 O MET 191 23.313 20.099 42.920 1.00 42.43 A 1431 N ILE 192 23.330 17.905 43.415 1.00 42.74 A 1432 CA ILE 192 22.972 18.124 44.815 1.00 43.28 A 1433 CB ILE 192 21.499 17.754 45.064 1.00 43.18 A 1434 CG2 ILE 192 20.596 18.639 44.219 1.00 43.15 A 1435 CG1 ILE 192 21.269 16.276 44.731 1.00 43.06 A 1436 CD1 ILE 192 19.848 15.798 45.004 1.00 42.93 A 1437 C ILE 192 23.831 17.349 45.809 1.00 43.79 A 1438 O ILE 192 23.538 17.324 47.004 1.00 43.59 A 1439 N GLY 193 24.882 16.710 45.310 1.00 44.53 A 1440 CA GLY 193 25.765 15.951 46.173 1.00 45.57 A 1441 C GLY 193 26.611 16.876 47.032 1.00 46.48 A 1442 O GLY 193 26.524 18.104 46.910 1.00 46.38 A 1443 N GLU 194 27.437 16.290 47.893 1.00 47.30 A 1444 CA GLU 194 28.286 17.064 48.795 1.00 48.24 A 1445 CB GLU 194 29.124 16.130 49.672 1.00 48.33 A 1446 CG GLU 194 30.122 16.877 50.545 1.00 48.74 A 1447 CD GLU 194 31.022 15.953 51.341 1.00 49.05 A 1448 OE1 GLU 194 31.022 14.731 51.068 1.00 49.21 A 1449 OE2 GLU 194 31.739 16.452 52.235 1.00 49.15 A 1450 C GLU 194 29.221 18.018 48.064 1.00 48.72 A 1451 O GLU 194 29.404 19.168 48.487 1.00 48.83 A 1452 N HIS 195 29.820 17.542 46.976 1.00 49.39 A 1453 CA HIS 195 30.745 18.365 46.214 1.00 50.10 A 1454 CB HIS 195 31.890 17.516 45.694 1.00 50.52 A 1455 CG HIS 195 32.670 16.884 46.798 1.00 50.96 A 1456 CD2 HIS 195 33.358 17.433 47.828 1.00 51.16 A 1457 ND1 HIS 195 32.695 15.523 46.999 1.00 51.15 A 1458 CE1 HIS 195 33.367 15.256 48.107 1.00 51.27 A 1459 NE2 HIS 195 33.781 16.398 48.628 1.00 51.39 A 1460 C HIS 195 30.137 19.185 45.105 1.00 50.36 A 1461 O HIS 195 30.821 19.604 44.172 1.00 50.51 A 1462 N ALA 196 28.834 19.412 45.213 1.00 50.55 A 1463 CA ALA 196 28.152 20.260 44.251 1.00 50.75 A 1464 CB ALA 196 26.732 19.779 43.998 1.00 50.64 A 1465 C ALA 196 28.135 21.636 44.926 1.00 50.88 A 1466 O ALA 196 27.440 21.850 45.924 1.00 50.94 A 1467 N VAL 197 28.899 22.570 44.377 1.00 51.05 A 1468 CA VAL 197 28.957 23.906 44.954 1.00 51.23 A 1469 CB VAL 197 30.044 24.754 44.263 1.00 51.40 A 1470 CG1 VAL 197 30.208 26.092 44.990 1.00 51.42 A 1471 CG2 VAL 197 31.362 23.995 44.264 1.00 51.45 A 1472 C VAL 197 27.626 24.658 44.920 1.00 51.21 A 1473 O VAL 197 27.168 25.152 45.958 1.00 51.19 A 1474 N SER 198 27.012 24.751 43.741 1.00 51.08 A 1475 CA SER 198 25.734 25.444 43.597 1.00 51.00 A 1476 CB SER 198 25.172 25.243 42.190 1.00 51.05 A 1477 OG SER 198 26.092 25.680 41.209 1.00 51.19 A 1478 C SER 198 24.737 24.911 44.615 1.00 50.92 A 1479 O SER 198 24.475 23.715 44.673 1.00 50.96 A 1480 N PRO 199 24.162 25.802 45.433 1.00 50.81 A 1481 CD PRO 199 24.663 27.150 45.771 1.00 50.78 A 1482 CA PRO 199 23.199 25.347 46.436 1.00 50.69 A 1483 CB PRO 199 23.581 26.178 47.649 1.00 50.77 A 1484 CG PRO 199 23.840 27.514 47.010 1.00 50.73 A 1485 C PRO 199 21.729 25.538 46.083 1.00 50.57 A 1486 O PRO 199 20.871 25.108 46.845 1.00 50.55 A 1487 N ASP 200 21.427 26.163 44.945 1.00 50.43 A 1488 CA ASP 200 20.029 26.416 44.601 1.00 50.41 A 1489 CB ASP 200 19.900 27.138 43.241 1.00 50.39 A 1490 CG ASP 200 20.503 26.363 42.078 1.00 50.36 A 1491 OD1 ASP 200 21.013 25.231 42.272 1.00 50.44 A 1492 OD2 ASP 200 20.469 26.895 40.945 1.00 50.25 A 1493 C ASP 200 19.117 25.193 44.653 1.00 50.34 A 1494 O ASP 200 18.030 25.260 45.232 1.00 50.33 A 1495 N LEU 201 19.550 24.081 44.073 1.00 50.31 A 1496 CA LEU 201 18.737 22.870 44.083 1.00 50.30 A 1497 CB LEU 201 19.338 21.825 43.140 1.00 50.26 A 1498 CG LEU 201 18.675 21.571 41.782 1.00 50.37 A 1499 CD1 LEU 201 18.002 22.802 41.250 1.00 50.33 A 1500 CD2 LEU 201 19.740 21.082 40.827 1.00 50.15 A 1501 C LEU 201 18.649 22.320 45.505 1.00 50.30 A 1502 O LEU 201 17.581 21.896 45.947 1.00 50.16 A 1503 N LYS 202 19.764 22.339 46.226 1.00 50.41 A 1504 CA LYS 202 19.757 21.839 47.594 1.00 50.68 A 1505 CB LYS 202 21.153 21.899 48.212 1.00 50.62 A 1506 CG LYS 202 22.165 20.990 47.549 1.00 50.62 A 1507 CD LYS 202 23.545 21.212 48.135 1.00 50.63 A 1508 CE LYS 202 24.597 20.387 47.416 1.00 50.71 A 1509 NZ LYS 202 25.982 20.706 47.872 1.00 50.72 A 1510 C LYS 202 18.795 22.657 48.442 1.00 50.90 A 1511 O LYS 202 18.030 22.102 49.227 1.00 50.78 A 1512 N ARG 203 18.825 23.973 48.273 1.00 51.26 A 1513 CA ARG 203 17.953 24.848 49.042 1.00 51.71 A 1514 CB ARG 203 18.305 26.315 48.792 1.00 52.21 A 1515 CG ARG 203 19.695 26.687 49.302 1.00 53.05 A 1516 CD ARG 203 20.058 28.139 49.001 1.00 53.78 A 1517 NE ARG 203 21.449 28.417 49.352 1.00 54.50 A 1518 CZ ARG 203 22.082 29.556 49.091 1.00 54.85 A 1519 NH1 ARG 203 21.457 30.554 48.470 1.00 55.02 A 1520 NH2 ARG 203 23.356 29.690 49.444 1.00 55.05 A 1521 C ARG 203 16.483 24.595 48.738 1.00 51.75 A 1522 O ARG 203 15.657 24.598 49.647 1.00 51.66 A 1523 N CYS 204 16.149 24.379 47.469 1.00 51.79 A 1524 CA CYS 204 14.761 24.105 47.112 1.00 51.94 A 1525 CB CYS 204 14.626 23.899 45.607 1.00 52.01 A 1526 SG CYS 204 14.550 25.400 44.646 1.00 52.24 A 1527 C CYS 204 14.276 22.847 47.820 1.00 52.00 A 1528 O CYS 204 13.200 22.833 48.413 1.00 51.91 A 1529 N LEU 205 15.087 21.794 47.739 1.00 52.10 A 1530 CA LEU 205 14.769 20.507 48.347 1.00 52.26 A 1531 CB LEU 205 15.884 19.495 48.065 1.00 51.94 A 1532 CG LEU 205 15.926 18.961 46.632 1.00 51.67 A 1533 CD1 LEU 205 17.242 18.276 46.391 1.00 51.47 A 1534 CD2 LEU 205 14.782 18.004 46.408 1.00 51.46 A 1535 C LEU 205 14.549 20.632 49.848 1.00 52.57 A 1536 O LEU 205 13.590 20.082 50.387 1.00 52.54 A 1537 N ALA 206 15.429 21.367 50.516 1.00 52.95 A 1538 CA ALA 206 15.311 21.549 51.956 1.00 53.42 A 1539 CB ALA 206 16.546 22.241 52.501 1.00 53.35 A 1540 C ALA 206 14.064 22.357 52.294 1.00 53.82 A 1541 O ALA 206 13.402 22.091 53.295 1.00 53.77 A 1542 N ALA 207 13.732 23.322 51.444 1.00 54.28 A 1543 CA ALA 207 12.568 24.165 51.679 1.00 54.86 A 1544 CB ALA 207 12.703 25.463 50.894 1.00 54.81 A 1545 C ALA 207 11.254 23.482 51.330 1.00 55.29 A 1546 O ALA 207 10.261 23.645 52.032 1.00 55.37 A 1547 N ARG 208 11.257 22.692 50.266 1.00 55.79 A 1548 CA ARG 208 10.044 22.023 49.813 1.00 56.35 A 1549 CB ARG 208 10.118 21.775 48.308 1.00 56.32 A 1550 CG ARG 208 10.421 23.006 47.500 1.00 56.51 A 1551 CD ARG 208 10.328 22.726 46.018 1.00 56.57 A 1552 NE ARG 208 9.498 23.740 45.392 1.00 56.83 A 1553 CZ ARG 208 8.566 23.498 44.487 1.00 56.83 A 1554 NH1 ARG 208 8.326 22.264 44.071 1.00 56.75 A 1555 NH2 ARG 208 7.844 24.509 44.029 1.00 57.04 A 1556 C ARG 208 9.652 20.711 50.475 1.00 56.77 A 1557 O ARG 208 8.472 20.463 50.682 1.00 56.73 A 1558 N LEU 209 10.628 19.868 50.789 1.00 57.33 A 1559 CA LEU 209 10.340 18.561 51.371 1.00 57.96 A 1560 CB LEU 209 11.627 17.731 51.446 1.00 57.90 A 1561 CG LEU 209 11.988 16.846 50.241 1.00 57.92 A 1562 CD1 LEU 209 10.950 15.745 50.075 1.00 57.91 A 1563 CD2 LEU 209 12.082 17.681 48.988 1.00 57.85 A 1564 C LEU 209 9.626 18.478 52.720 1.00 58.48 A 1565 O LEU 209 8.736 17.651 52.891 1.00 58.48 A 1566 N PRO 210 10.006 19.321 53.693 1.00 59.04 A 1567 CD PRO 210 11.051 20.359 53.644 1.00 59.19 A 1568 CA PRO 210 9.373 19.289 55.017 1.00 59.61 A 1569 CB PRO 210 9.895 20.561 55.671 1.00 59.46 A 1570 CG PRO 210 11.277 20.653 55.115 1.00 59.29 A 1571 C PRO 210 7.848 19.211 55.011 1.00 60.18 A 1572 O PRO 210 7.261 18.404 55.731 1.00 60.18 A 1573 N ALA 211 7.208 20.043 54.197 1.00 60.93 A 1574 CA ALA 211 5.752 20.055 54.118 1.00 61.74 A 1575 CB ALA 211 5.293 21.111 53.126 1.00 61.76 A 1576 C ALA 211 5.216 18.690 53.707 1.00 62.31 A 1577 O ALA 211 4.278 18.174 54.318 1.00 62.36 A 1578 N LEU 212 5.815 18.112 52.670 1.00 63.00 A 1579 CA LEU 212 5.400 16.805 52.169 1.00 63.72 A 1580 CB LEU 212 6.117 16.493 50.854 1.00 63.70 A 1581 CG LEU 212 5.865 17.446 49.687 1.00 63.70 A 1582 CD1 LEU 212 6.695 17.016 48.492 1.00 63.67 A 1583 CD2 LEU 212 4.386 17.446 49.338 1.00 63.66 A 1584 C LEU 212 5.680 15.694 53.175 1.00 64.26 A 1585 O LEU 212 4.844 14.819 53.400 1.00 64.29 A 1586 N LEU 213 6.860 15.734 53.781 1.00 64.95 A 1587 CA LEU 213 7.242 14.724 54.756 1.00 65.72 A 1588 CB LEU 213 8.704 14.917 55.171 1.00 65.66 A 1589 CG LEU 213 9.750 14.821 54.056 1.00 65.62 A 1590 CD1 LEU 213 11.138 14.973 54.653 1.00 65.58 A 1591 CD2 LEU 213 9.620 13.486 53.337 1.00 65.62 A 1592 C LEU 213 6.348 14.750 55.991 1.00 66.31 A 1593 O LEU 213 6.182 13.732 56.661 1.00 66.41 A 1594 N ASN 214 5.767 15.908 56.290 1.00 67.00 A 1595 CA ASN 214 4.900 16.033 57.457 1.00 67.73 A 1596 CB ASN 214 4.786 17.497 57.883 1.00 67.80 A 1597 CG ASN 214 5.957 17.939 58.733 1.00 68.01 A 1598 OD1 ASN 214 6.342 17.245 59.676 1.00 68.12 A 1599 ND2 ASN 214 6.526 19.099 58.415 1.00 68.17 A 1600 C ASN 214 3.508 15.439 57.273 1.00 68.14 A 1601 O ASN 214 2.852 15.078 58.249 1.00 68.29 A 1602 N GLU 215 3.055 15.336 56.029 1.00 68.60 A 1603 CA GLU 215 1.743 14.765 55.751 1.00 69.03 A 1604 CB GLU 215 .833 15.809 55.097 1.00 69.33 A 1605 CG GLU 215 1.427 16.486 53.877 1.00 69.76 A 1606 CD GLU 215 .434 17.403 53.188 1.00 70.11 A 1607 OE1 GLU 215 −.103 18.312 53.865 1.00 70.24 A 1608 OE2 GLU 215 .193 17.212 51.972 1.00 70.24 A 1609 C GLU 215 1.853 13.531 54.856 1.00 69.16 A 1610 OT1 GLU 215 1.410 13.597 53.686 1.00 69.27 A 1611 OT2 GLU 215 2.391 12.510 55.340 1.00 69.25 A 1612 CB SER 4 13.836 −22.661 42.351 1.00 61.80 B 1613 OG SER 4 13.171 −21.446 42.663 1.00 61.99 B 1614 C SER 4 15.637 −22.063 43.963 1.00 61.58 B 1615 O SER 4 14.784 −22.189 44.844 1.00 61.68 B 1616 N SER 4 16.030 −23.817 42.279 1.00 61.77 B 1617 CA SER 4 15.348 −22.517 42.541 1.00 61.72 B 1618 N ILE 5 16.847 −21.548 44.176 1.00 61.27 B 1619 CA ILE 5 17.287 −21.062 45.481 1.00 60.86 B 1620 CB ILE 5 16.681 −19.642 45.772 1.00 60.98 B 1621 CG2 ILE 5 15.161 −19.701 45.822 1.00 61.01 B 1622 CG1 ILE 5 17.242 −19.080 47.078 1.00 60.98 B 1623 CD1 ILE 5 16.423 −19.415 48.290 1.00 61.06 B 1624 C ILE 5 16.992 −22.049 46.619 1.00 60.46 B 1625 O ILE 5 15.847 −22.254 47.032 1.00 60.42 B 1626 N THR 6 18.060 −22.663 47.116 1.00 59.93 B 1627 CA THR 6 17.977 −23.649 48.182 1.00 59.38 B 1628 CB THR 6 18.791 −24.895 47.824 1.00 59.37 B 1629 OG1 THR 6 20.152 −24.511 47.588 1.00 59.31 B 1630 CG2 THR 6 18.235 −25.557 46.581 1.00 59.31 B 1631 C THR 6 18.530 −23.116 49.497 1.00 58.99 B 1632 O THR 6 19.154 −22.057 49.540 1.00 58.84 B 1633 N ALA 7 18.301 −23.867 50.569 1.00 58.52 B 1634 CA ALA 7 18.805 −23.488 51.874 1.00 58.11 B 1635 CB ALA 7 18.091 −24.278 52.966 1.00 58.10 B 1636 C ALA 7 20.291 −23.824 51.861 1.00 57.82 B 1637 O ALA 7 20.740 −24.647 51.063 1.00 57.74 B 1638 N ILE 8 21.055 −23.172 52.726 1.00 57.49 B 1639 CA ILE 8 22.484 −23.426 52.807 1.00 57.18 B 1640 CB ILE 8 23.315 −22.263 52.234 1.00 57.11 B 1641 CG2 ILE 8 24.796 −22.544 52.429 1.00 57.06 B 1642 CG1 ILE 8 23.003 −22.070 50.750 1.00 57.03 B 1643 CD1 ILE 8 23.673 −20.848 50.148 1.00 57.04 B 1644 C ILE 8 22.861 −23.583 54.263 1.00 57.06 B 1645 O ILE 8 22.430 −22.803 55.113 1.00 56.94 B 1646 N THR 9 23.667 −24.594 54.549 1.00 56.98 B 1647 CA THR 9 24.107 −24.828 55.912 1.00 56.95 B 1648 CB THR 9 23.763 −26.256 56.374 1.00 56.98 B 1649 OG1 THR 9 22.338 −26.427 56.349 1.00 57.05 B 1650 CG2 THR 9 24.273 −26.498 57.799 1.00 56.95 B 1651 C THR 9 25.606 −24.611 55.993 1.00 56.90 B 1652 O THR 9 26.365 −25.122 55.172 1.00 56.86 B 1653 N VAL 10 26.021 −23.823 56.974 1.00 56.82 B 1654 CA VAL 10 27.431 −23.534 57.178 1.00 56.83 B 1655 CB VAL 10 27.713 −22.017 57.053 1.00 56.70 B 1656 CG1 VAL 10 29.183 −21.726 57.328 1.00 56.57 B 1657 CG2 VAL 10 27.325 −21.535 55.669 1.00 56.63 B 1658 C VAL 10 27.784 −24.000 58.582 1.00 56.92 B 1659 O VAL 10 27.317 −23.428 59.565 1.00 56.96 B 1660 N GLU 11 28.588 −25.053 58.675 1.00 57.03 B 1661 CA GLU 11 28.989 −25.578 59.978 1.00 57.08 B 1662 CB GLU 11 29.940 −24.596 60.663 1.00 57.41 B 1663 CG GLU 11 31.291 −24.455 59.983 1.00 57.98 B 1664 CD GLU 11 32.137 −25.704 60.119 1.00 58.33 B 1665 OE1 GLU 11 32.355 −26.142 61.269 1.00 58.58 B 1666 OE2 GLU 11 32.585 −26.246 59.084 1.00 58.64 B 1667 C GLU 11 27.785 −25.833 60.879 1.00 56.87 B 1668 O GLU 11 27.719 −25.335 62.005 1.00 56.92 B 1669 N ASN 12 26.829 −26.603 60.374 1.00 56.59 B 1670 CA ASN 12 25.631 −26.936 61.135 1.00 56.21 B 1671 CB ASN 12 26.020 −27.661 62.428 1.00 56.68 B 1672 CG ASN 12 26.858 −28.903 62.165 1.00 57.06 B 1673 OD1 ASN 12 26.479 −29.765 61.364 1.00 57.33 B 1674 ND2 ASN 12 28.003 −29.000 62.834 1.00 57.28 B 1675 C ASN 12 24.733 −25.738 61.449 1.00 55.73 B 1676 O ASN 12 23.795 −25.854 62.234 1.00 55.69 B 1677 N LEU 13 25.027 −24.592 60.840 1.00 55.07 B 1678 CA LEU 13 24.212 −23.398 61.026 1.00 54.34 B 1679 CB LEU 13 25.093 −22.165 61.255 1.00 54.30 B 1680 CG LEU 13 25.882 −22.163 62.568 1.00 54.24 B 1681 CD1 LEU 13 26.883 −21.027 62.565 1.00 54.22 B 1682 CD2 LEU 13 24.925 −22.033 63.745 1.00 54.27 B 1683 C LEU 13 23.398 −23.256 59.744 1.00 53.90 B 1684 O LEU 13 23.912 −22.871 58.694 1.00 53.87 B 1685 N GLU 14 22.122 −23.589 59.839 1.00 53.26 B 1686 CA GLU 14 21.244 −23.546 58.683 1.00 52.74 B 1687 CB GLU 14 20.074 −24.504 58.910 1.00 53.34 B 1688 CG GLU 14 18.709 −23.907 58.609 1.00 54.36 B 1689 CD GLU 14 17.572 −24.812 59.041 1.00 54.97 B 1690 OE1 GLU 14 17.799 −26.045 59.135 1.00 55.41 B 1691 OE2 GLU 14 16.455 −24.288 59.276 1.00 55.26 B 1692 C GLU 14 20.707 −22.166 58.320 1.00 51.88 B 1693 O GLU 14 20.326 −21.376 59.188 1.00 51.76 B 1694 N TYR 15 20.672 −21.900 57.016 1.00 50.85 B 1695 CA TYR 15 20.145 −20.658 56.469 1.00 49.85 B 1696 CB TYR 15 21.212 −19.904 55.672 1.00 49.70 B 1697 CG TYR 15 22.216 −19.181 56.531 1.00 49.56 B 1698 CD1 TYR 15 23.274 −19.862 57.130 1.00 49.49 B 1699 CE1 TYR 15 24.177 −19.197 57.954 1.00 49.40 B 1700 CD2 TYR 15 22.086 −17.814 56.776 1.00 49.56 B 1701 CE2 TYR 15 22.976 −17.144 57.594 1.00 49.37 B 1702 CZ TYR 15 24.020 −17.836 58.180 1.00 49.43 B 1703 OH TYR 15 24.898 −17.155 58.991 1.00 49.23 B 1704 C TYR 15 18.998 −21.040 55.542 1.00 49.19 B 1705 O TYR 15 19.220 −21.455 54.409 1.00 49.13 B 1706 N PRO 16 17.754 −20.927 56.020 1.00 48.65 B 1707 CD PRO 16 17.283 −20.460 57.334 1.00 48.52 B 1708 CA PRO 16 16.626 −21.286 55.155 1.00 48.15 B 1709 CB PRO 16 15.404 −20.973 56.023 1.00 48.28 B 1710 CG PRO 16 15.914 −19.956 57.002 1.00 48.46 B 1711 C PRO 16 16.638 −20.517 53.836 1.00 47.65 B 1712 O PRO 16 17.183 −19.413 53.745 1.00 47.40 B 1713 N ALA 17 16.034 −21.120 52.819 1.00 47.10 B 1714 CA ALA 17 15.980 −20.533 51.488 1.00 46.55 B 1715 CB ALA 17 15.310 −21.513 50.523 1.00 46.52 B 1716 C ALA 17 15.227 −19.214 51.495 1.00 46.25 B 1717 O ALA 17 15.556 −18.293 50.745 1.00 46.11 B 1718 N VAL 18 14.219 −19.118 52.349 1.00 45.82 B 1719 CA VAL 18 13.421 −17.906 52.421 1.00 45.55 B 1720 CB VAL 18 12.079 −18.095 51.659 1.00 45.68 B 1721 CG1 VAL 18 11.269 −19.207 52.300 1.00 45.77 B 1722 CG2 VAL 18 11.279 −16.800 51.644 1.00 45.93 B 1723 C VAL 18 13.128 −17.518 53.862 1.00 45.24 B 1724 O VAL 18 13.072 −18.374 54.753 1.00 45.26 B 1725 N VAL 19 12.978 −16.224 54.098 1.00 44.65 B 1726 CA VAL 19 12.663 −15.758 55.435 1.00 44.13 B 1727 CB VAL 19 13.926 −15.336 56.272 1.00 44.19 B 1728 CG1 VAL 19 14.885 −16.498 56.411 1.00 44.28 B 1729 CG2 VAL 19 14.611 −14.157 55.633 1.00 44.26 B 1730 C VAL 19 11.764 −14.556 55.344 1.00 43.70 B 1731 O VAL 19 11.831 −13.779 54.386 1.00 43.46 B 1732 N THR 20 10.915 −14.421 56.350 1.00 43.23 B 1733 CA THR 20 10.018 −13.294 56.448 1.00 43.00 B 1734 CB THR 20 8.565 −13.743 56.490 1.00 43.00 B 1735 OG1 THR 20 8.244 −14.391 55.257 1.00 42.95 B 1736 CG2 THR 20 7.646 −12.540 56.691 1.00 42.85 B 1737 C THR 20 10.368 −12.563 57.723 1.00 42.81 B 1738 O THR 20 10.469 −13.157 58.791 1.00 42.81 B 1739 N SER 21 10.560 −11.262 57.603 1.00 42.69 B 1740 CA SER 21 10.938 −10.454 58.746 1.00 42.56 B 1741 CB SER 21 11.586 −9.148 58.277 1.00 42.51 B 1742 OG SER 21 11.680 −8.226 59.347 1.00 42.51 B 1743 C SER 21 9.843 −10.101 59.728 1.00 42.46 B 1744 O SER 21 8.838 −9.512 59.352 1.00 42.41 B 1745 N PRO 22 10.022 −10.464 61.004 1.00 42.42 B 1746 CD PRO 22 10.998 −11.374 61.631 1.00 42.39 B 1747 CA PRO 22 8.974 −10.107 61.959 1.00 42.32 B 1748 CB PRO 22 9.361 −10.890 63.208 1.00 42.38 B 1749 CG PRO 22 10.839 −11.014 63.087 1.00 42.48 B 1750 C PRO 22 9.035 −8.595 62.180 1.00 42.18 B 1751 O PRO 22 8.143 −8.013 62.780 1.00 42.18 B 1752 N VAL 23 10.100 −7.971 61.687 1.00 41.99 B 1753 CA VAL 23 10.272 −6.532 61.845 1.00 41.75 B 1754 CB VAL 23 11.781 −6.106 61.828 1.00 41.80 B 1755 CG1 VAL 23 11.887 −4.592 61.992 1.00 41.65 B 1756 CG2 VAL 23 12.534 −6.795 62.950 1.00 41.65 B 1757 C VAL 23 9.561 −5.743 60.754 1.00 41.72 B 1758 O VAL 23 8.772 −4.839 61.039 1.00 41.65 B 1759 N THR 24 9.839 −6.076 59.500 1.00 41.57 B 1760 CA THR 24 9.249 −5.340 58.386 1.00 41.68 B 1761 CB THR 24 10.304 −4.993 57.325 1.00 41.54 B 1762 OG1 THR 24 10.806 −6.209 56.755 1.00 41.46 B 1763 CG2 THR 24 11.457 −4.206 57.946 1.00 41.58 B 1764 C THR 24 8.135 −6.074 57.652 1.00 41.71 B 1765 O THR 24 7.444 −5.478 56.825 1.00 41.85 B 1766 N GLY 25 7.978 −7.358 57.934 1.00 41.81 B 1767 CA GLY 25 6.951 −8.127 57.253 1.00 41.91 B 1768 C GLY 25 7.378 −8.465 55.836 1.00 42.03 B 1769 O GLY 25 6.656 −9.152 55.115 1.00 41.88 B 1770 N LYS 26 8.552 −7.994 55.426 1.00 42.07 B 1771 CA LYS 26 9.050 −8.268 54.081 1.00 42.16 B 1772 CB LYS 26 10.130 −7.250 53.684 1.00 42.37 B 1773 CG LYS 26 9.616 −5.819 53.685 1.00 42.59 B 1774 CD LYS 26 10.656 −4.795 53.250 1.00 42.92 B 1775 CE LYS 26 10.030 −3.404 53.240 1.00 43.24 B 1776 NZ LYS 26 10.919 −2.330 52.711 1.00 43.72 B 1777 C LYS 26 9.614 −9.674 54.008 1.00 42.21 B 1778 O LYS 26 10.023 −10.238 55.022 1.00 42.21 B 1779 N SER 27 9.623 −10.235 52.803 1.00 42.25 B 1780 CA SER 27 10.142 −11.575 52.590 1.00 42.37 B 1781 CB SER 27 9.086 −12.447 51.901 1.00 42.48 B 1782 OG SER 27 7.938 −12.588 52.732 1.00 42.80 B 1783 C SER 27 11.406 −11.512 51.748 1.00 42.40 B 1784 O SER 27 11.514 −10.697 50.829 1.00 42.23 B 1785 N TYR 28 12.358 −12.379 52.064 1.00 42.45 B 1786 CA TYR 28 13.621 −12.408 51.351 1.00 42.71 B 1787 CB TYR 28 14.770 −11.927 52.243 1.00 42.79 B 1788 CG TYR 28 14.444 −10.811 53.208 1.00 42.90 B 1789 CD1 TYR 28 13.798 −11.073 54.416 1.00 43.14 B 1790 CE1 TYR 28 13.564 −10.052 55.344 1.00 43.31 B 1791 CD2 TYR 28 14.839 −9.500 52.943 1.00 42.89 B 1792 CE2 TYR 28 14.609 −8.477 53.855 1.00 42.94 B 1793 CZ TYR 28 13.977 −8.756 55.054 1.00 43.14 B 1794 OH TYR 28 13.790 −7.753 55.976 1.00 43.15 B 1795 C TYR 28 13.957 −13.815 50.933 1.00 42.80 B 1796 O TYR 28 13.404 −14.783 51.455 1.00 42.85 B 1797 N PHE 29 14.883 −13.924 49.994 1.00 42.97 B 1798 CA PHE 29 15.349 −15.224 49.551 1.00 43.23 B 1799 CB PHE 29 15.030 −15.442 48.070 1.00 42.93 B 1800 CG PHE 29 15.706 −14.477 47.153 1.00 42.69 B 1801 CD1 PHE 29 16.988 −14.731 46.678 1.00 42.62 B 1802 CD2 PHE 29 15.056 −13.313 46.750 1.00 42.65 B 1803 CE1 PHE 29 17.615 −13.840 45.814 1.00 42.52 B 1804 CE2 PHE 29 15.678 −12.415 45.886 1.00 42.52 B 1805 CZ PHE 29 16.959 −12.684 45.416 1.00 42.46 B 1806 C PHE 29 16.848 −15.224 49.810 1.00 43.57 B 1807 O PHE 29 17.490 −14.175 49.766 1.00 43.42 B 1808 N LEU 30 17.396 −16.394 50.106 1.00 44.16 B 1809 CA LEU 30 18.815 −16.522 50.390 1.00 44.89 B 1810 CB LEU 30 19.104 −17.902 50.977 1.00 44.66 B 1811 CG LEU 30 20.547 −18.188 51.383 1.00 44.61 B 1812 CD1 LEU 30 20.981 −17.233 52.491 1.00 44.49 B 1813 CD2 LEU 30 20.650 −19.638 51.855 1.00 44.61 B 1814 C LEU 30 19.673 −16.302 49.149 1.00 45.58 B 1815 O LEU 30 19.652 −17.102 48.212 1.00 45.50 B 1816 N GLY 31 20.428 −15.209 49.150 1.00 46.38 B 1817 CA GLY 31 21.290 −14.909 48.022 1.00 47.43 B 1818 C GLY 31 22.575 −15.705 48.108 1.00 48.27 B 1819 O GLY 31 23.185 −16.041 47.091 1.00 48.24 B 1820 N GLY 32 22.988 −16.013 49.333 1.00 49.11 B 1821 CA GLY 32 24.204 −16.777 49.533 1.00 50.38 B 1822 C GLY 32 24.594 −16.853 50.994 1.00 51.37 B 1823 O GLY 32 24.123 −16.066 51.813 1.00 51.30 B 1824 N ALA 33 25.449 −17.809 51.326 1.00 52.42 B 1825 CA ALA 33 25.904 −17.972 52.698 1.00 53.70 B 1826 CB ALA 33 25.011 −18.956 53.440 1.00 53.52 B 1827 C ALA 33 27.332 −18.481 52.671 1.00 54.67 B 1828 O ALA 33 27.717 −19.217 51.767 1.00 54.78 B 1829 N GLY 34 28.119 −18.081 53.658 1.00 55.80 B 1830 CA GLY 34 29.496 −18.525 53.712 1.00 57.28 B 1831 C GLY 34 30.030 −18.472 55.124 1.00 58.38 B 1832 O GLY 34 29.268 −18.376 56.085 1.00 58.39 B 1833 N GLU 35 31.348 −18.537 55.250 1.00 59.51 B 1834 CA GLU 35 31.990 −18.491 56.552 1.00 60.71 B 1835 CB GLU 35 32.602 −19.853 56.878 1.00 60.83 B 1836 CG GLU 35 33.477 −20.406 55.770 1.00 61.20 B 1837 CD GLU 35 33.783 −21.883 55.949 1.00 61.39 B 1838 OE1 GLU 35 33.051 −22.562 56.704 1.00 61.47 B 1839 OE2 GLU 35 34.746 −22.369 55.319 1.00 61.58 B 1840 C GLU 35 33.064 −17.415 56.576 1.00 61.50 B 1841 O GLU 35 33.589 −17.021 55.533 1.00 61.60 B 1842 N ARG 36 33.362 −16.932 57.774 1.00 62.40 B 1843 CA ARG 36 34.377 −15.913 57.984 1.00 63.41 B 1844 CB ARG 36 33.736 −14.531 58.136 1.00 63.24 B 1845 CG ARG 36 33.101 −13.984 56.863 1.00 63.15 B 1846 CD ARG 36 34.152 −13.434 55.898 1.00 63.03 B 1847 NE ARG 36 33.553 −12.696 54.787 1.00 62.88 B 1848 CZ ARG 36 32.857 −13.251 53.804 1.00 62.80 B 1849 NH1 ARG 36 32.666 −14.559 53.785 1.00 62.66 B 1850 NH2 ARG 36 32.357 −12.491 52.838 1.00 62.73 B 1851 C ARG 36 35.102 −16.282 59.267 1.00 64.23 B 1852 O ARG 36 34.516 −16.898 60.160 1.00 64.34 B 1853 N GLY 37 36.372 −15.916 59.367 1.00 65.15 B 1854 CA GLY 37 37.123 −16.241 60.564 1.00 66.33 B 1855 C GLY 37 38.520 −15.667 60.540 1.00 67.19 B 1856 O GLY 37 38.719 −14.513 60.155 1.00 67.22 B 1857 N LEU 38 39.489 −16.473 60.961 1.00 68.07 B 1858 CA LEU 38 40.879 −16.044 60.985 1.00 69.00 B 1859 CB LEU 38 41.364 −15.882 62.429 1.00 69.01 B 1860 CG LEU 38 40.616 −14.884 63.320 1.00 69.15 B 1861 CD1 LEU 38 41.184 −14.969 64.719 1.00 69.20 B 1862 CD2 LEU 38 40.743 −13.466 62.797 1.00 69.12 B 1863 C LEU 38 41.768 −17.052 60.267 1.00 69.61 B 1864 O LEU 38 41.450 −17.525 59.172 1.00 69.83 B 1865 N THR 39 42.885 −17.363 60.908 1.00 70.30 B 1866 CA THR 39 43.903 −18.295 60.432 1.00 70.92 B 1867 CB THR 39 44.605 −17.816 59.125 1.00 71.00 B 1868 OG1 THR 39 44.875 −16.413 59.212 1.00 71.11 B 1869 CG2 THR 39 43.750 −18.112 57.893 1.00 71.08 B 1870 C THR 39 44.933 −18.276 61.550 1.00 71.28 B 1871 O THR 39 45.518 −17.230 61.849 1.00 71.39 B 1872 N ILE 40 45.138 −19.414 62.191 1.00 71.65 B 1873 CA ILE 40 46.104 −19.475 63.272 1.00 71.98 B 1874 CB ILE 40 45.397 −19.519 64.649 1.00 72.07 B 1875 CG2 ILE 40 46.437 −19.577 65.768 1.00 72.13 B 1876 CG1 ILE 40 44.484 −18.293 64.789 1.00 72.16 B 1877 CD1 ILE 40 43.676 −18.247 66.072 1.00 72.19 B 1878 C ILE 40 46.996 −20.695 63.113 1.00 72.13 B 1879 O ILE 40 46.515 −21.829 63.098 1.00 72.14 B 1880 N GLU 41 48.296 −20.445 62.990 1.00 72.27 B 1881 CA GLU 41 49.280 −21.508 62.829 1.00 72.37 B 1882 CB GLU 41 49.115 −22.567 63.924 1.00 72.66 B 1883 CG GLU 41 49.074 −22.029 65.342 1.00 73.09 B 1884 CD GLU 41 48.860 −23.131 66.370 1.00 73.44 B 1885 OE1 GLU 41 48.404 −24.239 65.982 1.00 73.61 B 1886 OE2 GLU 41 49.131 −22.891 67.573 1.00 73.57 B 1887 C GLU 41 49.104 −22.154 61.461 1.00 72.24 B 1888 O GLU 41 49.422 −23.333 61.284 1.00 72.33 B 1889 N GLY 42 48.573 −21.388 60.509 1.00 72.00 B 1890 CA GLY 42 48.378 −21.897 59.163 1.00 71.65 B 1891 C GLY 42 47.039 −22.578 58.912 1.00 71.39 B 1892 O GLY 42 46.765 −23.036 57.800 1.00 71.45 B 1893 N ASN 43 46.198 −22.651 59.940 1.00 71.01 B 1894 CA ASN 43 44.884 −23.285 59.808 1.00 70.49 B 1895 CB ASN 43 44.699 −24.372 60.883 1.00 70.75 B 1896 CG ASN 43 45.721 −24.277 62.002 1.00 70.91 B 1897 OD1 ASN 43 45.379 −24.076 63.167 1.00 71.10 B 1898 ND2 ASN 43 46.993 −24.420 61.651 1.00 70.99 B 1899 C ASN 43 43.755 −22.266 59.908 1.00 69.94 B 1900 O ASN 43 43.570 −21.639 60.955 1.00 69.92 B 1901 N PHE 44 43.009 −22.091 58.819 1.00 69.17 B 1902 CA PHE 44 41.893 −21.147 58.803 1.00 68.34 B 1903 CB PHE 44 41.182 −21.163 57.449 1.00 68.55 B 1904 CG PHE 44 40.096 −20.129 57.331 1.00 68.73 B 1905 CD1 PHE 44 40.406 −18.811 57.018 1.00 68.84 B 1906 CD2 PHE 44 38.767 −20.457 57.583 1.00 68.82 B 1907 CE1 PHE 44 39.410 −17.832 56.961 1.00 68.92 B 1908 CE2 PHE 44 37.766 −19.482 57.527 1.00 68.87 B 1909 CZ PHE 44 38.091 −18.170 57.218 1.00 68.89 B 1910 C PHE 44 40.886 −21.537 59.878 1.00 67.59 B 1911 O PHE 44 40.255 −22.590 59.785 1.00 67.65 B 1912 N ILE 45 40.721 −20.692 60.891 1.00 66.57 B 1913 CA ILE 45 39.779 −21.003 61.958 1.00 65.46 B 1914 CB ILE 45 40.346 −20.598 63.336 1.00 65.65 B 1915 CG2 ILE 45 39.326 −20.907 64.432 1.00 65.67 B 1916 CG1 ILE 45 41.658 −21.348 63.592 1.00 65.76 B 1917 CD1 ILE 45 42.299 −21.037 64.924 1.00 65.89 B 1918 C ILE 45 38.444 −20.306 61.731 1.00 64.50 B 1919 O ILE 45 38.384 −19.080 61.627 1.00 64.36 B 1920 N LYS 46 37.383 −21.098 61.644 1.00 63.35 B 1921 CA LYS 46 36.040 −20.569 61.422 1.00 62.15 B 1922 CB LYS 46 35.113 −21.672 60.915 1.00 62.34 B 1923 CG LYS 46 35.632 −22.408 59.702 1.00 62.53 B 1924 CD LYS 46 34.607 −23.414 59.218 1.00 62.79 B 1925 CE LYS 46 35.092 −24.169 57.994 1.00 62.95 B 1926 NZ LYS 46 33.999 −24.987 57.410 1.00 63.14 B 1927 C LYS 46 35.451 −19.992 62.702 1.00 61.12 B 1928 O LYS 46 35.401 −20.669 63.727 1.00 61.07 B 1929 N PHE 47 34.997 −18.747 62.635 1.00 59.85 B 1930 CA PHE 47 34.398 −18.101 63.793 1.00 58.58 B 1931 CB PHE 47 35.069 −16.763 64.080 1.00 58.88 B 1932 CG PHE 47 36.336 −16.882 64.871 1.00 59.15 B 1933 CD1 PHE 47 37.512 −17.303 64.263 1.00 59.24 B 1934 CD2 PHE 47 36.352 −16.579 66.230 1.00 59.25 B 1935 CE1 PHE 47 38.691 −17.420 64.996 1.00 59.37 B 1936 CE2 PHE 47 37.530 −16.694 66.976 1.00 59.38 B 1937 CZ PHE 47 38.702 −17.115 66.354 1.00 59.40 B 1938 C PHE 47 32.909 −17.860 63.626 1.00 57.53 B 1939 O PHE 47 32.149 −17.967 64.585 1.00 57.43 B 1940 N THR 48 32.493 −17.526 62.411 1.00 56.23 B 1941 CA THR 48 31.094 −17.242 62.153 1.00 54.89 B 1942 CB THR 48 30.805 −15.740 62.306 1.00 54.93 B 1943 OG1 THR 48 31.464 −15.023 61.255 1.00 54.77 B 1944 CG2 THR 48 31.316 −15.221 63.639 1.00 54.93 B 1945 C THR 48 30.647 −17.628 60.753 1.00 53.91 B 1946 O THR 48 31.458 −17.826 59.848 1.00 53.77 B 1947 N ALA 49 29.337 −17.736 60.594 1.00 52.68 B 1948 CA ALA 49 28.736 −18.034 59.309 1.00 51.46 B 1949 CB ALA 49 27.720 −19.153 59.445 1.00 51.35 B 1950 C ALA 49 28.044 −16.722 58.953 1.00 50.62 B 1951 O ALA 49 27.607 −15.989 59.844 1.00 50.37 B 1952 N ILE 50 27.969 −16.412 57.667 1.00 49.66 B 1953 CA ILE 50 27.323 −15.186 57.238 1.00 48.82 B 1954 CB ILE 50 28.373 −14.144 56.789 1.00 49.03 B 1955 CG2 ILE 50 28.981 −14.557 55.462 1.00 49.23 B 1956 CG1 ILE 50 27.737 −12.761 56.694 1.00 49.22 B 1957 CD1 ILE 50 27.425 −12.141 58.065 1.00 49.28 B 1958 C ILE 50 26.387 −15.529 56.086 1.00 48.02 B 1959 O ILE 50 26.752 −16.270 55.179 1.00 48.00 B 1960 N GLY 51 25.164 −15.023 56.154 1.00 47.11 B 1961 CA GLY 51 24.206 −15.278 55.096 1.00 45.93 B 1962 C GLY 51 23.618 −13.957 54.652 1.00 45.12 B 1963 O GLY 51 23.386 −13.062 55.472 1.00 45.09 B 1964 N VAL 52 23.388 −13.819 53.354 1.00 44.10 B 1965 CA VAL 52 22.827 −12.590 52.826 1.00 43.04 B 1966 CB VAL 52 23.757 −11.940 51.777 1.00 43.10 B 1967 CG1 VAL 52 23.093 −10.694 51.196 1.00 42.81 B 1968 CG2 VAL 52 25.092 −11.592 52.410 1.00 42.98 B 1969 C VAL 52 21.489 −12.863 52.173 1.00 42.37 B 1970 O VAL 52 21.397 −13.662 51.241 1.00 42.33 B 1971 N TYR 53 20.456 −12.202 52.678 1.00 41.49 B 1972 CA TYR 53 19.118 −12.339 52.134 1.00 40.80 B 1973 CB TYR 53 18.089 −12.557 53.247 1.00 40.46 B 1974 CG TYR 53 18.154 −13.924 53.872 1.00 40.32 B 1975 CD1 TYR 53 19.024 −14.190 54.929 1.00 40.13 B 1976 CE1 TYR 53 19.104 −15.465 55.492 1.00 40.11 B 1977 CD2 TYR 53 17.361 −14.969 53.388 1.00 40.22 B 1978 CE2 TYR 53 17.435 −16.249 53.946 1.00 40.15 B 1979 CZ TYR 53 18.306 −26.488 54.992 1.00 40.03 B 1980 OH TYR 53 18.397 −17.752 55.521 1.00 39.76 B 1981 C TYR 53 18.746 −11.076 51.369 1.00 40.48 B 1982 O TYR 53 19.054 −9.967 51.807 1.00 40.28 B 1983 N LEU 54 18.080 −11.254 50.233 1.00 40.12 B 1984 CA LEU 54 17.634 −10.140 49.409 1.00 39.95 B 1985 CB LEU 54 18.195 −10.271 47.983 1.00 39.98 B 1986 CG LEU 54 19.728 −10.346 47.857 1.00 39.84 B 1987 CD1 LEU 54 20.131 −10.370 46.390 1.00 40.00 B 1988 CD2 LEU 54 20.353 −9.146 48.568 1.00 39.77 B 1989 C LEU 54 16.108 −10.168 49.373 1.00 39.95 B 1990 O LEU 54 15.512 −11.231 49.197 1.00 40.06 B 1991 N GLU 55 15.473 −9.015 49.554 1.00 39.84 B 1992 CA GLU 55 14.017 −8.954 49.520 1.00 39.83 B 1993 CB GLU 55 13.540 −7.505 49.619 1.00 39.82 B 1994 CG GLU 55 12.101 −7.355 50.074 1.00 39.79 B 1995 CD GLU 55 11.643 −5.912 50.094 1.00 40.01 B 1996 OE1 GLU 55 12.508 −5.004 50.125 1.00 39.92 B 1997 OE2 GLU 55 10.414 −5.683 50.089 1.00 40.17 B 1998 C GLU 55 13.558 −9.563 48.194 1.00 39.88 B 1999 O GLU 55 14.249 −9.448 47.178 1.00 39.68 B 2000 N ASP 56 12.397 −10.211 48.200 1.00 39.86 B 2001 CA ASP 56 11.899 −10.835 46.982 1.00 39.97 B 2002 CB ASP 56 10.522 −11.481 47.227 1.00 40.55 B 2003 CG ASP 56 9.551 −10.560 47.954 1.00 41.05 B 2004 OD1 ASP 56 9.792 −9.332 48.011 1.00 41.44 B 2005 OD2 ASP 56 8.526 −11.071 48.467 1.00 41.60 B 2006 C ASP 56 11.837 −9.887 45.781 1.00 39.66 B 2007 O ASP 56 12.165 −10.286 44.665 1.00 39.49 B 2008 N ILE 57 11.442 −8.636 46.002 1.00 39.41 B 2009 CA ILE 57 11.359 −7.678 44.900 1.00 39.38 B 2010 CB ILE 57 10.753 −6.333 45.350 1.00 39.45 B 2011 CG2 ILE 57 9.325 −6.548 45.835 1.00 39.63 B 2012 CG1 ILE 57 11.623 −5.697 46.441 1.00 39.32 B 2013 CD1 ILE 57 11.202 −4.280 46.795 1.00 39.16 B 2014 C ILE 57 12.702 −7.379 44.228 1.00 39.28 B 2015 O ILE 57 12.751 −6.685 43.213 1.00 39.13 B 2016 N ALA 58 13.792 −7.887 44.793 1.00 39.20 B 2017 CA ALA 58 15.101 −7.646 44.201 1.00 39.17 B 2018 CB ALA 58 16.196 −8.157 45.114 1.00 38.96 B 2019 C ALA 58 15.202 −8.314 42.828 1.00 39.20 B 2020 O ALA 58 15.903 −7.824 41.945 1.00 39.03 B 2021 N VAL 59 14.503 −9.431 42.646 1.00 39.35 B 2022 CA VAL 59 14.550 −10.130 41.360 1.00 39.57 B 2023 CB VAL 59 13.663 −11.400 41.368 1.00 39.70 B 2024 CG1 VAL 59 13.666 −12.059 39.979 1.00 39.75 B 2025 CG2 VAL 59 14.182 −12.380 42.413 1.00 39.86 B 2026 C VAL 59 14.107 −9.207 40.225 1.00 39.58 B 2027 O VAL 59 14.806 −9.072 39.216 1.00 39.68 B 2028 N ALA 60 12.960 −8.555 40.395 1.00 39.62 B 2029 CA ALA 60 12.453 −7.651 39.368 1.00 39.75 B 2030 CB ALA 60 11.058 −7.146 39.745 1.00 39.60 B 2031 C ALA 60 13.400 −6.470 39.168 1.00 39.86 B 2032 O ALA 60 13.582 −5.992 38.049 1.00 39.88 B 2033 N SER 61 14.010 −6.007 40.256 1.00 39.96 B 2034 CA SER 61 14.930 −4.883 40.182 1.00 40.10 B 2035 CB SER 61 15.312 −4.435 41.599 1.00 40.24 B 2036 OG SER 61 16.106 −3.268 41.565 1.00 40.32 B 2037 C SER 61 16.190 −5.238 39.387 1.00 40.20 B 2038 O SER 61 16.623 −4.491 38.511 1.00 39.93 B 2039 N LEU 62 16.767 −6.396 39.681 1.00 40.48 B 2040 CA LEU 62 17.984 −6.835 39.008 1.00 40.79 B 2041 CB LEU 62 18.678 −7.889 39.873 1.00 40.83 B 2042 CG LEU 62 19.092 −7.449 41.281 1.00 40.75 B 2043 CD1 LEU 62 19.447 −8.677 42.118 1.00 40.77 B 2044 CD2 LEU 62 20.276 −6.481 41.187 1.00 40.65 B 2045 C LEU 62 17.770 −7.403 37.597 1.00 41.21 B 2046 O LEU 62 18.699 −7.451 36.789 1.00 40.91 B 2047 N ALA 63 16.545 −7.829 37.306 1.00 41.76 B 2048 CA ALA 63 16.226 −8.428 36.014 1.00 42.24 B 2049 CB ALA 63 14.758 −8.854 35.987 1.00 42.07 B 2050 C ALA 63 16.526 −7.511 34.833 1.00 42.72 B 2051 O ALA 63 17.105 −7.942 33.838 1.00 42.73 B 2052 N ALA 64 16.134 −6.247 34.956 1.00 43.25 B 2053 CA ALA 64 16.348 −5.258 33.900 1.00 43.82 B 2054 CB ALA 64 16.090 −3.855 34.457 1.00 44.09 B 2055 C ALA 64 17.746 −5.323 33.289 1.00 43.99 B 2056 O ALA 64 17.905 −5.430 32.071 1.00 44.39 B 2057 N LYS 65 18.758 −5.296 34.143 1.00 43.95 B 2058 CA LYS 65 20.142 −5.309 33.691 1.00 44.01 B 2059 CB LYS 65 20.988 −4.413 34.604 1.00 43.63 B 2060 CG LYS 65 20.598 −2.951 34.605 1.00 43.43 B 2061 CD LYS 65 21.298 −2.185 35.727 1.00 43.05 B 2062 CE LYS 65 22.818 −2.233 35.597 1.00 42.89 B 2063 NZ LYS 65 23.513 −1.392 36.619 1.00 42.53 B 2064 C LYS 65 20.841 −6.659 33.620 1.00 44.17 B 2065 O LYS 65 21.731 −6.857 32.789 1.00 44.16 B 2066 N TRP 66 20.438 −7.590 34.475 1.00 44.43 B 2067 CA TRP 66 21.143 −8.856 34.560 1.00 44.80 B 2068 CB TRP 66 21.572 −9.045 36.017 1.00 44.39 B 2069 CG TRP 66 22.255 −7.805 36.513 1.00 44.15 B 2070 CD2 TRP 66 23.492 −7.269 36.030 1.00 43.98 B 2071 CE2 TRP 66 23.682 −6.018 36.662 1.00 43.97 B 2072 CE3 TRP 66 24.449 −7.716 35.108 1.00 43.86 B 2073 CD1 TRP 66 21.767 −6.893 37.408 1.00 44.00 B 2074 NE1 TRP 66 22.619 −5.815 37.502 1.00 43.86 B 2075 CZ2 TRP 66 24.799 −5.215 36.411 1.00 43.93 B 2076 CZ3 TRP 66 25.559 −6.916 34.857 1.00 43.93 B 2077 CH2 TRP 66 25.720 −5.676 35.504 1.00 43.94 B 2078 C TRP 66 20.528 −10.133 34.022 1.00 45.32 B 2079 O TRP 66 21.208 −11.157 33.954 1.00 45.20 B 2080 N LYS 67 19.261 −10.091 33.634 1.00 46.10 B 2081 CA LYS 67 18.626 −11.292 33.100 1.00 46.95 B 2082 CB LYS 67 17.176 −10.997 32.703 1.00 47.33 B 2083 CG LYS 67 16.432 −12.217 32.173 1.00 48.05 B 2084 CD LYS 67 14.974 −11.909 31.856 1.00 48.57 B 2085 CE LYS 67 14.286 −13.147 31.276 1.00 48.96 B 2086 NZ LYS 67 12.860 −12.897 30.895 1.00 49.49 B 2087 C LYS 67 19.410 −11.802 31.888 1.00 47.21 B 2088 O LYS 67 19.902 −11.013 31.083 1.00 47.25 B 2089 N GLY 68 19.555 −13.120 31.773 1.00 47.53 B 2090 CA GLY 68 20.264 −13.678 30.634 1.00 47.90 B 2091 C GLY 68 21.770 −13.809 30.773 1.00 48.24 B 2092 O GLY 68 22.407 −14.493 29.970 1.00 48.39 B 2093 N LYS 69 22.346 −13.159 31.780 1.00 48.41 B 2094 CA LYS 69 23.785 −13.222 32.014 1.00 48.60 B 2095 CB LYS 69 24.231 −12.018 32.841 1.00 48.88 B 2096 CG LYS 69 24.030 −10.681 32.143 1.00 49.27 B 2097 CD LYS 69 25.263 −10.277 31.361 1.00 49.77 B 2098 CE LYS 69 24.912 −9.242 30.306 1.00 50.02 B 2099 NZ LYS 69 23.867 −8.311 30.829 1.00 50.38 B 2100 C LYS 69 24.135 −14.510 32.754 1.00 48.62 B 2101 O LYS 69 23.409 −14.937 33.649 1.00 48.58 B 2102 N SER 70 25.247 −15.127 32.383 1.00 48.55 B 2103 CA SER 70 25.667 −16.358 33.031 1.00 48.64 B 2104 CB SER 70 26.741 −17.053 32.200 1.00 48.52 B 2105 OG SER 70 27.937 −16.293 32.193 1.00 48.58 B 2106 C SER 70 26.230 −16.045 34.411 1.00 48.68 B 2107 O SER 70 26.568 −14.897 34.709 1.00 48.64 B 2108 N SER 71 26.331 −17.070 35.248 1.00 48.70 B 2109 CA SER 71 26.870 −16.891 36.586 1.00 48.84 B 2110 CB SER 71 26.760 −18.197 37.382 1.00 48.74 B 2111 OG SER 71 25.400 −18.558 37.570 1.00 48.45 B 2112 C SER 71 28.328 −16.459 36.490 1.00 49.02 B 2113 O SER 71 28.801 −15.635 37.274 1.00 48.97 B 2114 N GLU 72 29.031 −17.015 35.510 1.00 49.24 B 2115 CA GLU 72 30.436 −16.702 35.299 1.00 49.50 B 2116 CB GLU 72 31.000 −17.565 34.167 1.00 50.10 B 2117 CG GLU 72 30.731 −19.074 34.306 1.00 51.11 B 2118 CD GLU 72 29.272 −19.459 34.048 1.00 51.70 B 2119 OE1 GLU 72 28.670 −18.953 33.078 1.00 52.50 B 2120 OE2 GLU 72 28.721 −20.286 34.803 1.00 52.20 B 2121 C GLU 72 30.600 −15.224 34.948 1.00 49.31 B 2122 O GLU 72 31.546 −14.567 35.397 1.00 49.38 B 2123 N GLU 73 29.682 −14.701 34.139 1.00 49.02 B 2124 CA GLU 73 29.761 −13.298 33.749 1.00 48.82 B 2125 CB GLU 73 28.801 −12.983 32.597 1.00 49.24 B 2126 CG GLU 73 29.011 −11.570 32.047 1.00 50.00 B 2127 CD GLU 73 28.126 −11.233 30.861 1.00 50.48 B 2128 OE1 GLU 73 27.590 −12.169 30.214 1.00 50.83 B 2129 OE2 GLU 73 27.983 −10.021 30.572 1.00 50.72 B 2130 C GLU 73 29.439 −12.401 34.937 1.00 48.32 B 2131 O GLU 73 30.153 −11.434 35.212 1.00 48.19 B 2132 N LEU 74 28.360 −12.723 35.640 1.00 47.81 B 2133 CA LEU 74 27.957 −11.938 36.800 1.00 47.37 B 2134 CB LEU 74 26.719 −12.559 37.455 1.00 47.26 B 2135 CG LEU 74 25.433 −12.529 36.630 1.00 47.22 B 2136 CD1 LEU 74 24.321 −13.215 37.400 1.00 47.15 B 2137 CD2 LEU 74 25.057 −11.085 36.320 1.00 47.11 B 2138 C LEU 74 29.078 −11.837 37.827 1.00 47.06 B 2139 O LEU 74 29.380 −10.754 38.324 1.00 46.87 B 2140 N LEU 75 29.705 −12.966 38.137 1.00 46.79 B 2141 CA LEU 75 30.771 −12.980 39.131 1.00 46.59 B 2142 CB LEU 75 31.366 −14.385 39.251 1.00 46.57 B 2143 CG LEU 75 32.465 −14.537 40.306 1.00 46.63 B 2144 CD1 LEU 75 31.920 −14.130 41.670 1.00 46.55 B 2145 CD2 LEU 75 32.967 −15.977 40.330 1.00 46.55 B 2146 C LEU 75 31.881 −11.969 38.849 1.00 46.50 B 2147 O LEU 75 32.430 −11.361 39.772 1.00 46.44 B 2148 N GLU 76 32.210 −11.779 37.574 1.00 46.41 B 2149 CA GLU 76 33.270 −10.844 37.205 1.00 46.29 B 2150 CB GLU 76 34.048 −11.381 35.995 1.00 47.04 B 2151 CG GLU 76 33.176 −12.071 34.936 1.00 48.20 B 2152 CD GLU 76 33.934 −12.441 33.654 1.00 48.84 B 2153 OE1 GLU 76 35.182 −12.559 33.696 1.00 49.33 B 2154 OE2 GLU 76 33.272 −12.626 32.600 1.00 49.21 B 2155 C GLU 76 32.775 −9.420 36.912 1.00 45.70 B 2156 O GLU 76 33.538 −8.580 36.438 1.00 45.76 B 2157 N THR 77 31.507 −9.145 37.199 1.00 44.89 B 2158 CA THR 77 30.948 −7.815 36.945 1.00 44.08 B 2159 CB THR 77 29.638 −7.920 36.156 1.00 44.08 B 2160 OG1 THR 77 29.855 −8.706 34.982 1.00 44.04 B 2161 CG2 THR 77 29.148 −6.536 35.760 1.00 44.00 B 2162 C THR 77 30.682 −7.043 38.230 1.00 43.44 B 2163 O THR 77 29.687 −7.281 38.913 1.00 43.38 B 2164 N LEU 78 31.573 −6.115 38.556 1.00 42.63 B 2165 CA LEU 78 31.425 −5.327 39.768 1.00 41.89 B 2166 CB LEU 78 32.560 −4.311 39.903 1.00 41.84 B 2167 CG LEU 78 33.971 −4.843 40.166 1.00 41.77 B 2168 CD1 LEU 78 34.936 −3.655 40.283 1.00 41.72 B 2169 CD2 LEU 78 33.984 −5.680 41.445 1.00 41.60 B 2170 C LEU 78 30.101 −4.591 39.796 1.00 41.50 B 2171 O LEU 78 29.509 −4.410 40.863 1.00 41.40 B 2172 N ASP 79 29.641 −4.166 38.625 1.00 40.76 B 2173 CA ASP 79 28.391 −3.436 38.537 1.00 40.19 B 2174 CB ASP 79 28.133 −2.994 37.099 1.00 39.93 B 2175 CG ASP 79 27.021 −1.973 37.005 1.00 39.73 B 2176 OD1 ASP 79 27.080 −.976 37.758 1.00 39.52 B 2177 OD2 ASP 79 26.094 −2.163 36.188 1.00 39.68 B 2178 C ASP 79 27.222 −4.274 39.046 1.00 39.95 B 2179 O ASP 79 26.277 −3.741 39.620 1.00 39.93 B 2180 N PHE 80 27.290 −5.584 38.833 1.00 39.65 B 2181 CA PHE 80 26.238 −6.479 39.298 1.00 39.49 B 2182 CB PHE 80 26.535 −7.914 38.848 1.00 39.69 B 2183 CG PHE 80 25.635 −8.947 39.471 1.00 39.88 B 2184 CD1 PHE 80 26.171 −9.978 40.232 1.00 39.84 B 2185 CD2 PHE 80 24.257 −8.893 39.290 1.00 39.82 B 2186 CE1 PHE 80 25.349 −10.944 40.804 1.00 39.98 B 2187 CE2 PHE 80 23.427 −9.854 39.857 1.00 39.99 B 2188 CZ PHE 80 23.971 −10.882 40.615 1.00 39.89 B 2189 C PHE 80 26.141 −6.419 40.822 1.00 39.23 B 2190 O PHE 80 25.053 −6.280 41.388 1.00 39.29 B 2191 N TYR 81 27.281 −6.513 41.494 1.00 38.84 B 2192 CA TYR 81 27.268 −6.466 42.947 1.00 38.60 B 2193 CB TYR 81 28.603 −6.960 43.500 1.00 38.64 B 2194 CG TYR 81 28.822 −8.407 43.146 1.00 38.74 B 2195 CD1 TYR 81 29.522 −8.766 41.993 1.00 38.91 B 2196 CE1 TYR 81 29.624 −10.097 41.598 1.00 38.98 B 2197 CD2 TYR 81 28.236 −9.418 43.901 1.00 38.88 B 2198 CE2 TYR 81 28.330 −10.756 43.514 1.00 38.83 B 2199 CZ TYR 81 29.026 −11.085 42.362 1.00 39.00 B 2200 OH TYR 81 29.124 −12.401 41.968 1.00 39.16 B 2201 C TYR 81 26.915 −5.090 43.491 1.00 38.39 B 2202 O TYR 81 26.368 −4.983 44.582 1.00 38.23 B 2203 N ARG 82 27.209 −4.036 42.735 1.00 38.27 B 2204 CA ARG 82 26.855 −2.700 43.194 1.00 38.20 B 2205 CB ARG 82 27.430 −1.615 42.277 1.00 38.62 B 2206 CG ARG 82 28.948 −1.499 42.343 1.00 39.18 B 2207 CD ARG 82 29.415 −.058 42.150 1.00 39.76 B 2208 NE ARG 82 30.865 .032 42.296 1.00 40.24 B 2209 CZ ARG 82 31.732 −.267 41.333 1.00 40.54 B 2210 NH1 ARG 82 31.294 −.660 40.142 1.00 40.61 B 2211 NH2 ARG 82 33.039 −.202 41.573 1.00 40.71 B 2212 C ARG 82 25.335 −2.610 43.218 1.00 37.97 B 2213 O ARG 82 24.762 −2.015 44.131 1.00 37.74 B 2214 N ASP 83 24.683 −3.209 42.220 1.00 37.78 B 2215 CA ASP 83 23.223 −3.189 42.175 1.00 37.70 B 2216 CB ASP 83 22.690 −3.795 40.873 1.00 37.72 B 2217 CG ASP 83 22.784 −2.835 39.699 1.00 37.89 B 2218 OD1 ASP 83 22.683 −1.604 39.917 1.00 38.14 B 2219 OD2 ASP 83 22.931 −3.306 38.556 1.00 37.83 B 2220 C ASP 83 22.664 −3.960 43.366 1.00 37.51 B 2221 O ASP 83 21.676 −3.559 43.958 1.00 37.53 B 2222 N ILE 84 23.300 −5.066 43.725 1.00 37.44 B 2223 CA ILE 84 22.825 −5.832 44.863 1.00 37.47 B 2224 CB ILE 84 23.555 −7.184 44.978 1.00 37.40 B 2225 CG2 ILE 84 23.210 −7.854 46.304 1.00 37.28 B 2226 CG1 ILE 84 23.161 −8.074 43.795 1.00 37.35 B 2227 CD1 ILE 84 23.852 −9.419 43.769 1.00 37.46 B 2228 C ILE 84 23.021 −5.035 46.150 1.00 37.47 B 2229 O ILE 84 22.121 −4.953 46.976 1.00 37.59 B 2230 N ILE 85 24.191 −4.428 46.311 1.00 37.43 B 2231 CA ILE 85 24.481 −3.646 47.511 1.00 37.40 B 2232 CB ILE 85 25.951 −3.156 47.512 1.00 37.47 B 2233 CG2 ILE 85 26.181 −2.201 48.678 1.00 37.29 B 2234 CG1 ILE 85 26.905 −4.352 47.594 1.00 37.36 B 2235 CD1 ILE 85 28.350 −3.996 47.266 1.00 37.35 B 2236 C ILE 85 23.583 −2.418 47.684 1.00 37.50 B 2237 O ILE 85 23.046 −2.178 48.770 1.00 37.33 B 2238 N SER 86 23.420 −1.636 46.620 1.00 37.58 B 2239 CA SER 86 22.611 −.426 46.719 1.00 37.89 B 2240 CB SER 86 23.423 .769 46.218 1.00 38.16 B 2241 OG SER 86 24.648 .859 46.930 1.00 38.50 B 2242 C SER 86 21.277 −.494 45.982 1.00 37.85 B 2243 O SER 86 20.663 .541 45.697 1.00 37.88 B 2244 N GLY 87 20.833 −1.712 45.684 1.00 37.83 B 2245 CA GLY 87 19.570 −1.901 44.993 1.00 37.79 B 2246 C GLY 87 18.395 −1.401 45.814 1.00 37.71 B 2247 O GLY 87 18.460 −1.388 47.042 1.00 37.67 B 2248 N PRO 88 17.297 −.997 45.157 1.00 37.71 B 2249 CD PRO 88 17.139 −1.053 43.692 1.00 37.67 B 2250 CA PRO 88 16.080 −.479 45.791 1.00 37.83 B 2251 CB PRO 88 15.341 .154 44.618 1.00 37.69 B 2252 CG PRO 88 15.643 −.807 43.510 1.00 37.64 B 2253 C PRO 88 15.244 −1.541 46.500 1.00 37.94 B 2254 O PRO 88 14.056 −1.713 46.216 1.00 37.87 B 2255 N PHE 89 15.870 −2.244 47.431 1.00 38.07 B 2256 CA PHE 89 15.194 −3.290 48.180 1.00 38.25 B 2257 CB PHE 89 15.063 −4.550 47.324 1.00 38.10 B 2258 CG PHE 89 16.319 −4.907 46.578 1.00 38.02 B 2259 CD1 PHE 89 17.376 −5.543 47.225 1.00 37.76 B 2260 CD2 PHE 89 16.449 −4.589 45.220 1.00 37.82 B 2261 CE1 PHE 89 18.543 −5.858 46.533 1.00 37.81 B 2262 CE2 PHE 89 17.612 −4.899 44.521 1.00 37.79 B 2263 CZ PHE 89 18.662 −5.536 45.180 1.00 37.99 B 2264 C PHE 89 15.977 −3.590 49.441 1.00 38.46 B 2265 O PHE 89 17.172 −3.309 49.529 1.00 38.42 B 2266 N GLU 90 15.296 −4.172 50.413 1.00 38.66 B 2267 CA GLU 90 15.917 −4.485 51.681 1.00 38.95 B 2268 CB GLU 90 14.829 −4.737 52.723 1.00 39.19 B 2269 CG GLU 90 15.307 −4.613 54.146 1.00 39.63 B 2270 CD GLU 90 14.167 −4.448 55.112 1.00 39.63 B 2271 OE1 GLU 90 13.588 −5.471 55.534 1.00 39.90 B 2272 OE2 GLU 90 13.842 −3.291 55.441 1.00 39.82 B 2273 C GLU 90 16.828 −5.692 51.591 1.00 39.01 B 2274 O GLU 90 16.562 −6.632 50.836 1.00 39.01 B 2275 N LYS 91 17.929 −5.646 52.333 1.00 38.99 B 2276 CA LYS 91 18.838 −6.778 52.389 1.00 39.10 B 2277 CB LYS 91 20.238 −6.431 51.873 1.00 39.04 B 2278 CG LYS 91 20.282 −5.909 50.435 1.00 39.18 B 2279 CD LYS 91 20.188 −4.385 50.407 1.00 39.16 B 2280 CE LYS 91 20.294 −3.844 48.993 1.00 39.09 B 2281 NZ LYS 91 20.328 −2.354 49.026 1.00 39.27 B 2282 C LYS 91 18.892 −7.138 53.865 1.00 39.23 B 2283 O LYS 91 18.820 −6.273 54.738 1.00 39.21 B 2284 N LEU 92 18.986 −8.423 54.146 1.00 39.40 B 2285 CA LEU 92 19.034 −8.876 55.522 1.00 39.58 B 2286 CB LEU 92 17.745 −9.628 55.873 1.00 39.62 B 2287 CG LEU 92 17.642 −10.163 57.300 1.00 39.75 B 2288 CD1 LEU 92 17.771 −9.027 58.303 1.00 39.86 B 2289 CD2 LEU 92 16.304 −10.867 57.465 1.00 39.95 B 2290 C LEU 92 20.230 −9.790 55.639 1.00 39.65 B 2291 O LEU 92 20.281 −10.847 55.013 1.00 39.55 B 2292 N ILE 93 21.199 −9.370 56.439 1.00 39.89 B 2293 CA ILE 93 22.412 −10.145 56.627 1.00 40.18 B 2294 CB ILE 93 23.651 −9.237 56.540 1.00 40.36 B 2295 CG2 ILE 93 24.919 −10.075 56.614 1.00 40.39 B 2296 CG1 ILE 93 23.623 −8.436 55.237 1.00 40.47 B 2297 CD1 ILE 93 24.658 −7.332 55.209 1.00 41.03 B 2298 C ILE 93 22.390 −10.806 57.996 1.00 40.37 B 2299 O ILE 93 22.205 −10.136 59.011 1.00 40.20 B 2300 N ARG 94 22.561 −12.122 58.030 1.00 40.70 B 2301 CA ARG 94 22.578 −12.813 59.304 1.00 41.11 B 2302 CB ARG 94 21.511 −13.905 59.378 1.00 41.34 B 2303 CG ARG 94 21.391 −14.492 60.776 1.00 41.86 B 2304 CD ARG 94 21.838 −15.945 60.864 1.00 42.47 B 2305 NE ARG 94 20.839 −16.837 60.298 1.00 42.93 B 2306 CZ ARG 94 20.929 −18.163 60.275 1.00 43.21 B 2307 NH1 ARG 94 21.980 −18.783 60.794 1.00 43.37 B 2308 NH2 ARG 94 19.954 −18.873 59.721 1.00 43.51 B 2309 C ARG 94 23.930 −13.447 59.561 1.00 41.29 B 2310 O ARG 94 24.403 −14.272 58.782 1.00 41.31 B 2311 N GLY 95 24.559 −13.031 60.650 1.00 41.47 B 2312 CA GLY 95 25.831 −13.608 61.021 1.00 41.78 B 2313 C GLY 95 25.524 −14.484 62.217 1.00 42.11 B 2314 O GLY 95 24.856 −14.038 63.148 1.00 41.97 B 2315 N SER 96 25.968 −15.734 62.180 1.00 42.50 B 2316 CA SER 96 25.753 −16.659 63.286 1.00 43.05 B 2317 CB SER 96 24.888 −17.839 62.845 1.00 43.13 B 2318 OG SER 96 23.562 −17.402 62.592 1.00 43.17 B 2319 C SER 96 27.116 −17.147 63.742 1.00 43.42 B 2320 O SER 96 27.966 −17.479 62.920 1.00 43.38 B 2321 N LYS 97 27.326 −17.181 65.053 1.00 43.78 B 2322 CA LYS 97 28.613 −17.601 65.594 1.00 44.33 B 2323 CB LYS 97 28.782 −17.055 67.016 1.00 43.97 B 2324 CG LYS 97 29.334 −15.636 67.063 1.00 43.61 B 2325 CD LYS 97 28.487 −14.660 66.262 1.00 43.15 B 2326 CE LYS 97 29.113 −13.271 66.287 1.00 42.99 B 2327 NZ LYS 97 28.302 −12.273 65.553 1.00 42.83 B 2328 C LYS 97 28.888 −19.094 65.599 1.00 44.89 B 2329 O LYS 97 28.017 −19.907 65.920 1.00 45.01 B 2330 N ILE 98 30.111 −19.446 65.218 1.00 45.54 B 2331 CA ILE 98 30.547 −20.832 65.227 1.00 46.25 B 2332 CB ILE 98 31.464 −21.135 64.031 1.00 46.31 B 2333 CG2 ILE 98 32.038 −22.541 64.159 1.00 46.33 B 2334 CG1 ILE 98 30.663 −20.998 62.732 1.00 46.41 B 2335 CD1 ILE 98 31.501 −21.063 61.460 1.00 46.56 B 2336 C ILE 98 31.313 −20.958 66.546 1.00 46.69 B 2337 O ILE 98 31.185 −21.955 67.258 1.00 46.81 B 2338 N ARG 99 32.093 −19.928 66.862 1.00 47.22 B 2339 CA ARG 99 32.839 −19.859 68.115 1.00 47.79 B 2340 CB ARG 99 34.341 −19.653 67.876 1.00 48.66 B 2341 CG ARG 99 35.039 −20.829 67.200 1.00 50.10 B 2342 CD ARG 99 36.549 −20.590 67.108 1.00 51.29 B 2343 NE ARG 99 37.194 −21.602 66.272 1.00 52.52 B 2344 CZ ARG 99 37.376 −22.872 66.630 1.00 52.95 B 2345 NH1 ARG 99 36.967 −23.293 67.821 1.00 53.15 B 2346 NH2 ARG 99 37.957 −23.727 65.791 1.00 53.37 B 2347 C ARG 99 32.288 −18.656 68.873 1.00 47.56 B 2348 O ARG 99 31.841 −17.685 68.263 1.00 47.62 B 2349 N GLU 100 32.320 −18.721 70.192 1.00 47.26 B 2350 CA GLU 100 31.806 −17.635 71.011 1.00 46.82 B 2351 CB GLU 100 31.807 −18.042 72.482 1.00 47.00 B 2352 CG GLU 100 31.353 −16.941 73.415 1.00 47.32 B 2353 CD GLU 100 31.344 −17.385 74.861 1.00 47.64 B 2354 OE1 GLU 100 32.328 −18.032 75.291 1.00 47.96 B 2355 OE2 GLU 100 30.361 −17.083 75.569 1.00 47.60 B 2356 C GLU 100 32.613 −16.363 70.831 1.00 46.46 B 2357 O GLU 100 33.840 −16.388 70.784 1.00 46.42 B 2358 N LEU 101 31.911 −15.244 70.730 1.00 45.98 B 2359 CA LEU 101 32.542 −13.945 70.558 1.00 45.58 B 2360 CB LEU 101 32.636 −13.575 69.074 1.00 45.63 B 2361 CG LEU 101 33.666 −14.276 68.178 1.00 45.72 B 2362 CD1 LEU 101 33.383 −13.944 66.717 1.00 45.66 B 2363 CD2 LEU 101 35.072 −13.833 68.564 1.00 45.72 B 2364 C LEU 101 31.690 −12.913 71.262 1.00 45.28 B 2365 O LEU 101 30.467 −12.924 71.133 1.00 45.19 B 2366 N SER 102 32.328 −12.029 72.016 1.00 44.93 B 2367 CA SER 102 31.591 −10.982 72.693 1.00 44.64 B 2368 CB SER 102 32.470 −10.285 73.728 1.00 44.63 B 2369 OG SER 102 33.484 −9.537 73.091 1.00 44.35 B 2370 C SER 102 31.216 −9.995 71.598 1.00 44.52 B 2371 O SER 102 31.745 −10.065 70.481 1.00 44.43 B 2372 N GLY 103 30.309 −9.080 71.913 1.00 44.33 B 2373 CA GLY 103 29.899 −8.098 70.931 1.00 44.23 B 2374 C GLY 103 31.084 −7.273 70.461 1.00 44.21 B 2375 O GLY 103 31.335 −7.179 69.257 1.00 43.93 B 2376 N PRO 104 31.835 −6.657 71.391 1.00 44.23 B 2377 CD PRO 104 31.601 −6.583 72.847 1.00 44.17 B 2378 CA PRO 104 32.995 −5.845 71.003 1.00 44.29 B 2379 CB PRO 104 33.556 −5.384 72.349 1.00 44.28 B 2380 CG PRO 104 32.315 −5.298 73.219 1.00 44.22 B 2381 C PRO 104 34.018 −6.640 70.184 1.00 44.41 B 2382 O PRO 104 34.577 −6.132 69.204 1.00 44.34 B 2383 N GLU 105 34.252 −7.888 70.583 1.00 44.57 B 2384 CA GLU 105 35.211 −8.744 69.889 1.00 44.86 B 2385 CB GLU 105 35.313 −10.107 70.589 1.00 45.23 B 2386 CG GLU 105 36.169 −10.108 71.864 1.00 45.87 B 2387 CD GLU 105 35.997 −11.374 72.700 1.00 46.21 B 2388 OE1 GLU 105 35.568 −12.412 72.141 1.00 46.29 B 2389 OE2 GLU 105 36.303 −11.328 73.919 1.00 46.63 B 2390 C GLU 105 34.812 −8.948 68.431 1.00 44.86 B 2391 O GLU 105 35.628 −8.784 67.521 1.00 44.82 B 2392 N TYR 106 33.550 −9.306 68.214 1.00 44.74 B 2393 CA TYR 106 33.044 −9.542 66.869 1.00 44.72 B 2394 CB TYR 106 31.650 −10.170 66.924 1.00 44.32 B 2395 CG TYR 106 30.890 −10.017 65.623 1.00 43.89 B 2396 CD1 TYR 106 31.158 −10.844 64.531 1.00 43.61 B 2397 CE1 TYR 106 30.499 −10.660 63.312 1.00 43.43 B 2398 CD2 TYR 106 29.943 −9.002 65.467 1.00 43.68 B 2399 CE2 TYR 106 29.284 −8.807 64.259 1.00 43.45 B 2400 CZ TYR 106 29.565 −9.634 63.185 1.00 43.44 B 2401 OH TYR 106 28.934 −9.412 61.981 1.00 43.19 B 2402 C TYR 106 32.969 −8.265 66.044 1.00 44.85 B 2403 O TYR 106 33.394 −8.239 64.895 1.00 44.94 B 2404 N SER 107 32.428 −7.207 66.637 1.00 45.03 B 2405 CA SER 107 32.253 −5.940 65.943 1.00 45.36 B 2406 CB SER 107 31.366 −5.008 66.772 1.00 45.31 B 2407 OG SER 107 32.028 −4.577 67.948 1.00 45.62 B 2408 C SER 107 33.525 −5.192 65.554 1.00 45.54 B 2409 O SER 107 33.516 −4.416 64.589 1.00 45.33 B 2410 N ARG 108 34.614 −5.411 66.289 1.00 45.82 B 2411 CA ARG 108 35.862 −4.707 65.998 1.00 46.19 B 2412 CB ARG 108 37.010 −5.245 66.860 1.00 46.83 B 2413 CG ARG 108 38.393 −4.627 66.567 1.00 47.97 B 2414 CD ARG 108 39.447 −5.200 67.510 1.00 48.98 B 2415 NE ARG 108 39.228 −6.632 67.687 1.00 50.09 B 2416 CZ ARG 108 39.654 −7.573 66.848 1.00 50.65 B 2417 NH1 ARG 108 40.350 −7.241 65.764 1.00 50.78 B 2418 NH2 ARG 108 39.341 −8.851 67.074 1.00 51.14 B 2419 C ARG 108 36.253 −4.758 64.522 1.00 46.00 B 2420 O ARG 108 36.381 −3.721 63.881 1.00 45.86 B 2421 N LYS 109 36.429 −5.957 63.982 1.00 45.88 B 2422 CA LYS 109 36.824 −6.105 62.585 1.00 45.94 B 2423 CB LYS 109 37.112 −7.574 62.269 1.00 46.46 B 2424 CG LYS 109 37.774 −7.804 60.906 1.00 47.39 B 2425 CD LYS 109 39.186 −7.201 60.841 1.00 48.10 B 2426 CE LYS 109 39.836 −7.472 59.481 1.00 48.60 B 2427 NZ LYS 109 41.268 −7.022 59.421 1.00 49.19 B 2428 C LYS 109 35.760 −5.565 61.630 1.00 45.63 B 2429 O LYS 109 36.079 −4.855 60.670 1.00 45.55 B 2430 N VAL 110 34.497 −5.886 61.894 1.00 45.16 B 2431 CA VAL 110 33.410 −5.414 61.051 1.00 44.73 B 2432 CB VAL 110 32.028 −5.853 61.593 1.00 44.71 B 2433 CG1 VAL 110 30.907 −5.239 60.748 1.00 44.63 B 2434 CG2 VAL 110 31.929 −7.369 61.574 1.00 44.80 B 2435 C VAL 110 33.432 −3.894 60.944 1.00 44.42 B 2436 O VAL 110 33.358 −3.342 59.846 1.00 44.16 B 2437 N MET 111 33.544 −3.219 62.081 1.00 44.16 B 2438 CA MET 111 33.568 −1.766 62.091 1.00 44.20 B 2439 CB MET 111 33.521 −1.241 63.526 1.00 44.23 B 2440 CG MET 111 32.216 −1.562 64.241 1.00 44.37 B 2441 SD MET 111 32.026 −.698 65.800 1.00 44.68 B 2442 CE MET 111 33.149 −1.674 66.836 1.00 44.57 B 2443 C MET 111 34.795 −1.223 61.365 1.00 44.19 B 2444 O MET 111 34.722 −.204 60.676 1.00 44.09 B 2445 N GLU 112 35.919 −1.913 61.523 1.00 44.23 B 2446 CA GLU 112 37.159 −1.521 60.865 1.00 44.24 B 2447 CB GLU 112 38.259 −2.551 61.153 1.00 44.74 B 2448 CG GLU 112 39.006 −2.344 62.463 1.00 45.81 B 2449 CD GLU 112 40.078 −3.403 62.683 1.00 46.41 B 2450 OE1 GLU 112 40.665 −3.867 61.674 1.00 47.00 B 2451 OE2 GLU 112 40.345 −3.760 63.857 1.00 46.99 B 2452 C GLU 112 36.935 −1.453 59.359 1.00 43.86 B 2453 O GLU 112 37.242 −.454 58.710 1.00 43.75 B 2454 N ASN 113 36.394 −2.544 58.824 1.00 43.53 B 2455 CA ASN 113 36.133 −2.674 57.400 1.00 43.29 B 2456 CB ASN 113 35.655 −4.086 57.066 1.00 43.39 B 2457 CG ASN 113 36.726 −5.126 57.312 1.00 43.65 B 2458 OD1 ASN 113 37.915 −4.822 57.266 1.00 43.96 B 2459 ND2 ASN 113 36.318 −6.355 57.557 1.00 43.65 B 2460 C ASN 113 35.121 −1.656 56.927 1.00 43.03 B 2461 O ASN 113 35.241 −1.141 55.821 1.00 43.01 B 2462 N CYS 114 34.126 −1.361 57.755 1.00 42.64 B 2463 CA CYS 114 33.133 −.374 57.364 1.00 42.52 B 2464 CB CYS 114 31.963 −.336 58.359 1.00 42.13 B 2465 SG CYS 114 30.837 −1.760 58.238 1.00 41.13 B 2466 C CYS 114 33.771 1.005 57.283 1.00 42.70 B 2467 O CYS 114 33.579 1.724 56.308 1.00 42.60 B 2468 N VAL 115 34.526 1.372 58.313 1.00 42.95 B 2469 CA VAL 115 35.173 2.676 58.337 1.00 43.35 B 2470 CB VAL 115 35.923 2.917 59.668 1.00 43.35 B 2471 CG1 VAL 115 36.626 4.277 59.630 1.00 43.27 B 2472 CG2 VAL 115 34.945 2.870 60.836 1.00 43.13 B 2473 C VAL 115 36.157 2.822 57.177 1.00 43.62 B 2474 O VAL 115 36.255 3.893 56.577 1.00 43.60 B 2475 N ALA 116 36.882 1.751 56.864 1.00 43.95 B 2476 CA ALA 116 37.840 1.787 55.764 1.00 44.42 B 2477 CB ALA 116 38.616 .471 55.688 1.00 44.43 B 2478 C ALA 116 37.087 2.033 54.456 1.00 44.80 B 2479 O ALA 116 37.505 2.844 53.627 1.00 44.82 B 2480 N HIS 117 35.971 1.335 54.270 1.00 45.02 B 2481 CA HIS 117 35.182 1.517 53.059 1.00 45.36 B 2482 CB HIS 117 33.978 .577 53.042 1.00 45.33 B 2483 CG HIS 117 32.889 1.029 52.119 1.00 45.35 B 2484 CD2 HIS 117 31.675 1.569 52.371 1.00 45.40 B 2485 ND1 HIS 117 33.023 1.008 50.746 1.00 45.38 B 2486 CE1 HIS 117 31.935 1.516 50.194 1.00 45.41 B 2487 NE2 HIS 117 31.100 1.865 51.156 1.00 45.50 B 2488 C HIS 117 34.669 2.946 52.951 1.00 45.61 B 2489 O HIS 117 34.781 3.581 51.895 1.00 45.59 B 2490 N LEU 118 34.094 3.435 54.044 1.00 45.87 B 2491 CA LEU 118 33.529 4.775 54.088 1.00 46.40 B 2492 CB LEU 118 32.919 5.026 55.469 1.00 46.21 B 2493 CG LEU 118 31.703 4.141 55.786 1.00 46.17 B 2494 CD1 LEU 118 31.313 4.277 57.258 1.00 46.06 B 2495 CD2 LEU 118 30.539 4.535 54.877 1.00 46.03 B 2496 C LEU 118 34.555 5.854 53.746 1.00 46.94 B 2497 O LEU 118 34.243 6.817 53.032 1.00 46.82 B 2498 N LYS 119 35.772 5.700 54.257 1.00 47.41 B 2499 CA LYS 119 36.820 6.667 53.958 1.00 48.19 B 2500 CB LYS 119 38.048 6.421 54.845 1.00 48.24 B 2501 CG LYS 119 37.827 6.759 56.311 1.00 48.48 B 2502 CD LYS 119 39.053 6.419 57.167 1.00 48.89 B 2503 CE LYS 119 38.859 6.868 58.620 1.00 49.08 B 2504 NZ LYS 119 39.997 6.460 59.507 1.00 49.31 B 2505 C LYS 119 37.184 6.505 52.480 1.00 48.60 B 2506 O LYS 119 37.322 7.480 51.746 1.00 48.64 B 2507 N SER 120 37.309 5.256 52.046 1.00 49.03 B 2508 CA SER 120 37.644 4.951 50.665 1.00 49.52 B 2509 CB SER 120 37.553 3.445 50.432 1.00 49.70 B 2510 OG SER 120 37.802 3.131 49.075 1.00 50.40 B 2511 C SER 120 36.742 5.669 49.665 1.00 49.72 B 2512 O SER 120 37.223 6.277 48.709 1.00 49.97 B 2513 N VAL 121 35.432 5.599 49.877 1.00 49.77 B 2514 CA VAL 121 34.492 6.234 48.965 1.00 49.62 B 2515 CB VAL 121 33.164 5.439 48.885 1.00 49.60 B 2516 CG1 VAL 121 33.443 4.016 48.403 1.00 49.53 B 2517 CG2 VAL 121 32.477 5.422 50.241 1.00 49.55 B 2518 C VAL 121 34.203 7.678 49.347 1.00 49.56 B 2519 O VAL 121 33.225 8.271 48.886 1.00 49.65 B 2520 N GLY 122 35.059 8.237 50.199 1.00 49.41 B 2521 CA GLY 122 34.902 9.620 50.617 1.00 49.04 B 2522 C GLY 122 33.617 9.988 51.334 1.00 48.88 B 2523 O GLY 122 33.131 11.113 51.202 1.00 48.83 B 2524 N THR 123 33.061 9.057 52.101 1.00 48.62 B 2525 CA THR 123 31.839 9.339 52.836 1.00 48.45 B 2526 CB THR 123 30.636 8.568 52.257 1.00 48.43 B 2527 OG1 THR 123 30.897 7.159 52.307 1.00 48.37 B 2528 CG2 THR 123 30.391 8.986 50.804 1.00 48.46 B 2529 C THR 123 32.002 8.979 54.306 1.00 48.42 B 2530 O THR 123 31.298 8.115 54.833 1.00 48.20 B 2531 N TYR 124 32.950 9.636 54.967 1.00 48.36 B 2532 CA TYR 124 33.165 9.382 56.380 1.00 48.37 B 2533 CB TYR 124 34.393 8.499 56.607 1.00 48.68 B 2534 CG TYR 124 34.443 7.935 58.013 1.00 49.05 B 2535 CD1 TYR 124 33.410 7.121 58.491 1.00 49.13 B 2536 CE1 TYR 124 33.417 6.634 59.796 1.00 49.25 B 2537 CD2 TYR 124 35.492 8.246 58.880 1.00 49.15 B 2538 CE2 TYR 124 35.507 7.762 60.193 1.00 49.40 B 2539 CZ TYR 124 34.465 6.959 60.643 1.00 49.37 B 2540 OH TYR 124 34.458 6.493 61.941 1.00 49.50 B 2541 C TYR 124 33.313 10.677 57.152 1.00 48.26 B 2542 O TYR 124 34.405 11.031 57.595 1.00 48.28 B 2543 N GLY 125 32.197 11.383 57.302 1.00 48.00 B 2544 CA GLY 125 32.196 12.632 58.035 1.00 47.72 B 2545 C GLY 125 31.789 12.370 59.471 1.00 47.48 B 2546 O GLY 125 31.771 11.218 59.910 1.00 47.44 B 2547 N ASP 126 31.455 13.425 60.206 1.00 47.17 B 2548 CA ASP 126 31.060 13.259 61.597 1.00 46.93 B 2549 CB ASP 126 30.799 14.613 62.260 1.00 47.09 B 2550 CG ASP 126 32.027 15.509 62.267 1.00 47.31 B 2551 OD1 ASP 126 33.165 14.988 62.358 1.00 47.24 B 2552 OD2 ASP 126 31.842 16.738 62.191 1.00 47.53 B 2553 C ASP 126 29.809 12.397 61.717 1.00 46.61 B 2554 O ASP 126 29.712 11.554 62.605 1.00 46.57 B 2555 N ALA 127 28.852 12.617 60.821 1.00 46.15 B 2556 CA ALA 127 27.609 11.857 60.839 1.00 45.71 B 2557 CB ALA 127 26.721 12.273 59.675 1.00 45.75 B 2558 C ALA 127 27.884 10.361 60.781 1.00 45.32 B 2559 O ALA 127 27.304 9.590 61.545 1.00 45.23 B 2560 N GLU 128 28.777 9.958 59.883 1.00 44.95 B 2561 CA GLU 128 29.122 8.550 59.733 1.00 44.76 B 2562 CB GLU 128 29.907 8.324 58.438 1.00 44.56 B 2563 CG GLU 128 29.083 8.501 57.157 1.00 44.48 B 2564 CD GLU 128 28.644 9.932 56.933 1.00 44.62 B 2565 OE1 GLU 128 29.523 10.822 56.881 1.00 44.61 B 2566 OE2 GLU 128 27.424 10.175 56.809 1.00 44.46 B 2567 C GLU 128 29.920 8.035 60.928 1.00 44.73 B 2568 O GLU 128 29.732 6.894 61.369 1.00 44.60 B 2569 N ALA 129 30.816 8.869 61.446 1.00 44.62 B 2570 CA ALA 129 31.619 8.484 62.602 1.00 44.60 B 2571 CB ALA 129 32.627 9.587 62.938 1.00 44.61 B 2572 C ALA 129 30.677 8.243 63.780 1.00 44.49 B 2573 O ALA 129 30.813 7.267 64.515 1.00 44.56 B 2574 N GLU 130 29.714 9.137 63.951 1.00 44.45 B 2575 CA GLU 130 28.739 9.011 65.026 1.00 44.48 B 2576 CB GLU 130 27.858 10.256 65.078 1.00 45.14 B 2577 CG GLU 130 28.598 11.486 65.547 1.00 46.35 B 2578 CD GLU 130 27.778 12.747 65.390 1.00 47.07 B 2579 OE1 GLU 130 26.533 12.654 65.497 1.00 47.63 B 2580 OE2 GLU 130 28.379 13.830 65.179 1.00 47.40 B 2581 C GLU 130 27.869 7.770 64.829 1.00 44.02 B 2582 O GLU 130 27.526 7.081 65.791 1.00 43.83 B 2583 N ALA 131 27.503 7.500 63.580 1.00 43.48 B 2584 CA ALA 131 26.693 6.330 63.271 1.00 43.03 B 2585 CB ALA 131 26.338 6.303 61.778 1.00 42.94 B 2586 C ALA 131 27.486 5.080 63.649 1.00 42.74 B 2587 O ALA 131 26.938 4.141 64.221 1.00 42.68 B 2588 N MET 132 28.779 5.072 63.337 1.00 42.40 B 2589 CA MET 132 29.617 3.925 63.658 1.00 42.20 B 2590 CB MET 132 30.981 4.051 62.983 1.00 42.10 B 2591 CG MET 132 30.948 3.863 61.473 1.00 41.85 B 2592 SD MET 132 30.030 2.369 60.961 1.00 41.55 B 2593 CE MET 132 31.020 1.045 61.669 1.00 41.45 B 2594 C MET 132 29.798 3.746 65.167 1.00 42.24 B 2595 O MET 132 30.032 2.636 65.642 1.00 42.08 B 2596 N GLN 133 29.687 4.838 65.914 1.00 42.30 B 2597 CA GLN 133 29.817 4.777 67.366 1.00 42.53 B 2598 CB GLN 133 30.058 6.169 67.950 1.00 42.87 B 2599 CG GLN 133 30.362 6.163 69.436 1.00 43.75 B 2600 CD GLN 133 31.485 5.202 69.789 1.00 44.32 B 2601 OE1 GLN 133 32.478 5.088 69.056 1.00 45.00 B 2602 NE2 GLN 133 31.342 4.510 70.920 1.00 44.68 B 2603 C GLN 133 28.514 4.210 67.915 1.00 42.32 B 2604 O GLN 133 28.507 3.468 68.898 1.00 42.35 B 2605 N LYS 134 27.409 4.573 67.276 1.00 42.03 B 2606 CA LYS 134 26.112 4.063 67.689 1.00 41.86 B 2607 CB LYS 134 25.005 4.728 66.878 1.00 41.92 B 2608 CG LYS 134 23.614 4.381 67.347 1.00 42.04 B 2609 CD LYS 134 22.575 5.239 66.649 1.00 42.11 B 2610 CE LYS 134 21.173 4.882 67.129 1.00 42.16 B 2611 NZ LYS 134 20.148 5.808 66.572 1.00 42.17 B 2612 C LYS 134 26.156 2.566 67.411 1.00 41.63 B 2613 O LYS 134 25.701 1.756 68.215 1.00 41.61 B 2614 N PHE 135 26.730 2.219 66.263 1.00 41.35 B 2615 CA PHE 135 26.898 .832 65.829 1.00 41.15 B 2616 CB PHE 135 27.687 .831 64.513 1.00 41.27 B 2617 CG PHE 135 27.818 −.518 63.857 1.00 41.32 B 2618 CD1 PHE 135 27.058 −.826 62.731 1.00 41.46 B 2619 CD2 PHE 135 28.757 −1.441 64.305 1.00 41.29 B 2620 CE1 PHE 135 27.231 −2.032 62.051 1.00 41.47 B 2621 CE2 PHE 135 28.941 −2.650 63.637 1.00 41.40 B 2622 CZ PHE 135 28.177 −2.947 62.504 1.00 41.48 B 2623 C PHE 135 27.672 .068 66.917 1.00 40.97 B 2624 O PHE 135 27.218 −.966 67.422 1.00 40.60 B 2625 N ALA 136 28.846 .590 67.271 1.00 40.77 B 2626 CA ALA 136 29.692 −.025 68.295 1.00 40.78 B 2627 CB ALA 136 30.960 .810 68.493 1.00 40.74 B 2628 C ALA 136 28.966 −.182 69.634 1.00 40.78 B 2629 O ALA 136 29.035 −1.235 70.260 1.00 40.59 B 2630 N GLU 137 28.281 .871 70.073 1.00 40.99 B 2631 CA GLU 137 27.557 .836 71.343 1.00 41.43 B 2632 CB GLU 137 26.864 2.176 71.621 1.00 42.20 B 2633 CG GLU 137 27.792 3.326 72.023 1.00 43.67 B 2634 CD GLU 137 28.600 3.022 73.277 1.00 44.55 B 2635 OE1 GLU 137 27.989 2.739 74.335 1.00 45.15 B 2636 OE2 GLU 137 29.854 3.062 73.204 1.00 45.31 B 2637 C GLU 137 26.514 −.278 71.396 1.00 41.11 B 2638 O GLU 137 26.279 −.857 72.454 1.00 41.14 B 2639 N ALA 138 25.888 −.577 70.262 1.00 40.77 B 2640 CA ALA 138 24.858 −1.616 70.210 1.00 40.34 B 2641 CB ALA 138 24.142 −1.581 68.856 1.00 40.48 B 2642 C ALA 138 25.408 −3.005 70.466 1.00 40.04 B 2643 O ALA 138 24.699 −3.863 70.986 1.00 39.85 B 2644 N PHE 139 26.665 −3.243 70.102 1.00 39.74 B 2645 CA PHE 139 27.269 −4.561 70.314 1.00 39.63 B 2646 CB PHE 139 28.345 −4.853 69.260 1.00 39.43 B 2647 CG PHE 139 27.811 −5.179 67.890 1.00 39.21 B 2648 CD1 PHE 139 27.460 −4.167 67.005 1.00 39.17 B 2649 CD2 PHE 139 27.685 −6.506 67.484 1.00 39.03 B 2650 CE1 PHE 139 26.989 −4.469 65.723 1.00 39.05 B 2651 CE2 PHE 139 27.216 −6.822 66.211 1.00 39.04 B 2652 CZ PHE 139 26.867 −5.804 65.326 1.00 38.97 B 2653 C PHE 139 27.918 −4.716 71.683 1.00 39.74 B 2654 O PHE 139 28.161 −5.836 72.125 1.00 39.68 B 2655 N LYS 140 28.210 −3.606 72.352 1.00 39.82 B 2656 CA LYS 140 28.884 −3.681 73.650 1.00 40.23 B 2657 CB LYS 140 29.142 −2.274 74.193 1.00 40.29 B 2658 CG LYS 140 30.232 −1.521 73.430 1.00 40.72 B 2659 CD LYS 140 30.644 −.267 74.150 1.00 41.15 B 2660 CE LYS 140 31.701 .493 73.377 1.00 41.49 B 2661 NZ LYS 140 31.992 1.789 74.052 1.00 41.94 B 2662 C LYS 140 28.231 −4.543 74.729 1.00 40.23 B 2663 O LYS 140 28.914 −5.361 75.355 1.00 40.34 B 2664 N PRO 141 26.922 −4.415 74.954 1.00 40.31 B 2665 CD PRO 141 25.967 −3.418 74.428 1.00 40.32 B 2666 CA PRO 141 26.297 −5.235 76.005 1.00 40.41 B 2667 CB PRO 141 25.105 −4.395 76.414 1.00 40.39 B 2668 CG PRO 141 24.665 −3.838 75.091 1.00 40.45 B 2669 C PRO 141 25.877 −6.623 75.540 1.00 40.40 B 2670 O PRO 141 25.189 −7.342 76.263 1.00 40.38 B 2671 N VAL 142 26.320 −7.000 74.349 1.00 40.41 B 2672 CA VAL 142 25.954 −8.285 73.778 1.00 40.49 B 2673 CB VAL 142 25.438 −8.098 72.316 1.00 40.45 B 2674 CG1 VAL 142 25.140 −9.451 71.680 1.00 40.38 B 2675 CG2 VAL 142 24.196 −7.220 72.314 1.00 40.30 B 2676 C VAL 142 27.108 −9.278 73.754 1.00 40.66 B 2677 O VAL 142 28.268 −8.904 73.599 1.00 40.50 B 2678 N ASN 143 26.771 −10.551 73.919 1.00 40.87 B 2679 CA ASN 143 27.760 −11.614 73.836 1.00 41.19 B 2680 CB ASN 143 28.002 −12.273 75.193 1.00 41.32 B 2681 CG ASN 143 29.095 −13.323 75.129 1.00 41.65 B 2682 OD1 ASN 143 30.185 −13.068 74.598 1.00 41.53 B 2683 ND2 ASN 143 28.816 −14.511 75.668 1.00 41.69 B 2684 C ASN 143 27.166 −12.629 72.871 1.00 41.36 B 2685 O ASN 143 25.950 −12.825 72.856 1.00 41.16 B 2686 N PHE 144 28.010 −13.271 72.069 1.00 41.61 B 2687 CA PHE 144 27.518 −14.243 71.098 1.00 42.05 B 2688 CB PHE 144 27.889 −13.834 69.662 1.00 41.83 B 2689 CG PHE 144 27.275 −12.542 69.202 1.00 41.67 B 2690 CD1 PHE 144 28.017 −11.364 69.198 1.00 41.68 B 2691 CD2 PHE 144 25.964 −12.509 68.735 1.00 41.57 B 2692 CE1 PHE 144 27.461 −10.166 68.730 1.00 41.53 B 2693 CE2 PHE 144 25.401 −11.328 68.270 1.00 41.42 B 2694 CZ PHE 144 26.153 −10.149 68.266 1.00 41.44 B 2695 C PHE 144 28.030 −15.658 71.312 1.00 42.43 B 2696 O PHE 144 29.108 −16.011 70.833 1.00 42.44 B 2697 N PRO 145 27.273 −16.486 72.040 1.00 42.74 B 2698 CD PRO 145 26.074 −16.216 72.850 1.00 42.84 B 2699 CA PRO 145 27.741 −17.857 72.241 1.00 42.99 B 2700 CB PRO 145 26.766 −18.408 73.281 1.00 42.99 B 2701 CG PRO 145 26.266 −17.161 73.984 1.00 43.06 B 2702 C PRO 145 27.564 −18.516 70.875 1.00 43.22 B 2703 O PRO 145 26.905 −17.959 69.991 1.00 43.21 B 2704 N PRO 146 28.154 −19.697 70.669 1.00 43.41 B 2705 CD PRO 146 28.924 −20.582 71.555 1.00 43.53 B 2706 CA PRO 146 27.956 −20.302 69.351 1.00 43.39 B 2707 CB PRO 146 28.683 −21.641 69.467 1.00 43.46 B 2708 CG PRO 146 28.663 −21.930 70.936 1.00 43.66 B 2709 C PRO 146 26.462 −20.447 69.063 1.00 43.32 B 2710 O PRO 146 25.681 −20.780 69.954 1.00 43.39 B 2711 N GLY 147 26.063 −20.160 67.828 1.00 43.08 B 2712 CA GLY 147 24.658 −20.264 67.473 1.00 42.71 B 2713 C GLY 147 23.951 −18.930 67.579 1.00 42.36 B 2714 O GLY 147 22.958 −18.687 66.893 1.00 42.50 B 2715 N ALA 148 24.455 −18.058 68.440 1.00 41.98 B 2716 CA ALA 148 23.857 −16.739 68.605 1.00 41.52 B 2717 CB ALA 148 24.539 −15.994 69.742 1.00 41.54 B 2718 C ALA 148 24.037 −15.998 67.281 1.00 41.26 B 2719 O ALA 148 24.953 −16.299 66.511 1.00 41.14 B 2720 N SER 149 23.177 −15.020 67.015 1.00 40.78 B 2721 CA SER 149 23.253 −14.316 65.749 1.00 40.27 B 2722 CB SER 149 22.179 −14.852 64.790 1.00 40.27 B 2723 OG SER 149 22.238 −16.259 64.676 1.00 40.39 B 2724 C SER 149 23.087 −12.816 65.823 1.00 39.88 B 2725 O SER 149 22.569 −12.264 66.800 1.00 39.88 B 2726 N VAL 150 23.544 −12.169 64.761 1.00 39.35 B 2727 CA VAL 150 23.392 −10.743 64.608 1.00 38.82 B 2728 CB VAL 150 24.735 −9.980 64.563 1.00 38.79 B 2729 CG1 VAL 150 25.670 −10.565 63.504 1.00 38.52 B 2730 CG2 VAL 150 24.453 −8.512 64.276 1.00 38.56 B 2731 C VAL 150 22.687 −10.599 63.274 1.00 38.60 B 2732 O VAL 150 22.990 −11.308 62.308 1.00 38.40 B 2733 N PHE 151 21.717 −9.703 63.232 1.00 38.32 B 2734 CA PHE 151 20.978 −9.478 62.009 1.00 38.25 B 2735 CB PHE 151 19.490 −9.775 62.229 1.00 38.31 B 2736 CG PHE 151 19.165 −11.244 62.290 1.00 38.50 B 2737 CD1 PHE 151 18.844 −11.943 61.130 1.00 38.57 B 2738 CD2 PHE 151 19.196 −11.931 63.500 1.00 38.67 B 2739 CE1 PHE 151 18.554 −13.308 61.173 1.00 38.62 B 2740 CE2 PHE 151 18.908 −13.304 63.559 1.00 38.64 B 2741 CZ PHE 151 18.587 −13.989 62.393 1.00 38.59 B 2742 C PHE 151 21.150 −8.034 61.587 1.00 38.12 B 2743 O PHE 151 20.826 −7.121 62.351 1.00 37.93 B 2744 N TYR 152 21.681 −7.837 60.383 1.00 37.98 B 2745 CA TYR 152 21.847 −6.502 59.837 1.00 37.97 B 2746 CB TYR 152 23.189 −6.340 59.109 1.00 37.80 B 2747 CG TYR 152 24.421 −6.563 59.959 1.00 37.59 B 2748 CD1 TYR 152 25.033 −7.812 60.017 1.00 37.45 B 2749 CE1 TYR 152 26.202 −8.006 60.756 1.00 37.50 B 2750 CD2 TYR 152 25.002 −5.512 60.667 1.00 37.53 B 2751 CE2 TYR 152 26.170 −5.696 61.408 1.00 37.41 B 2752 CZ TYR 152 26.760 −6.941 61.442 1.00 37.42 B 2753 OH TYR 152 27.922 −7.121 62.145 1.00 37.70 B 2754 C TYR 152 20.720 −6.338 58.827 1.00 38.12 B 2755 O TYR 152 20.657 −7.048 57.822 1.00 37.99 B 2756 N ARG 153 19.818 −5.415 59.110 1.00 38.21 B 2757 CA ARG 153 18.709 −5.153 58.223 1.00 38.55 B 2758 CB ARG 153 17.428 −4.982 59.041 1.00 39.13 B 2759 CG ARG 153 16.155 −4.771 58.226 1.00 39.93 B 2760 CD ARG 153 15.067 −4.167 59.126 1.00 40.78 B 2761 NE ARG 153 14.543 −2.975 58.488 1.00 41.84 B 2762 CZ ARG 153 14.398 −1.795 59.070 1.00 42.20 B 2763 NH1 ARG 153 14.730 −1.609 60.341 1.00 42.29 B 2764 NH2 ARG 153 13.926 −.784 58.352 1.00 43.17 B 2765 C ARG 153 19.056 −3.861 57.489 1.00 38.47 B 2766 O ARG 153 18.983 −2.774 58.062 1.00 38.45 B 2767 N GLN 154 19.459 −3.989 56.232 1.00 38.38 B 2768 CA GLN 154 19.817 −2.830 55.432 1.00 38.51 B 2769 CB GLN 154 20.923 −3.170 54.444 1.00 38.40 B 2770 CG GLN 154 21.385 −1.991 53.598 1.00 38.16 B 2771 CD GLN 154 22.381 −2.404 52.527 1.00 38.27 B 2772 OE1 GLN 154 23.205 −3.307 52.736 1.00 37.97 B 2773 NE2 GLN 154 22.319 −1.738 51.375 1.00 37.83 B 2774 C GLN 154 18.593 −2.356 54.663 1.00 38.75 B 2775 O GLN 154 18.205 −2.949 53.655 1.00 38.54 B 2776 N SER 155 17.987 −1.286 55.149 1.00 39.11 B 2777 CA SER 155 16.814 −.708 54.519 1.00 39.50 B 2778 CB SER 155 16.042 .135 55.532 1.00 39.57 B 2779 OG SER 155 15.119 .981 54.876 1.00 40.10 B 2780 C SER 155 17.237 .159 53.358 1.00 39.71 B 2781 O SER 155 18.228 .889 53.423 1.00 39.77 B 2782 N PRO 156 16.479 .113 52.249 1.00 39.90 B 2783 CD PRO 156 15.293 −.728 51.977 1.00 39.90 B 2784 CA PRO 156 16.861 .946 51.099 1.00 40.02 B 2785 CB PRO 156 16.011 .379 49.948 1.00 39.96 B 2786 CG PRO 156 14.811 −.238 50.609 1.00 39.92 B 2787 C PRO 156 16.629 2.434 51.368 1.00 40.13 B 2788 O PRO 156 17.058 3.294 50.606 1.00 40.33 B 2789 N ASP 157 15.970 2.717 52.490 1.00 40.28 B 2790 CA ASP 157 15.667 4.081 52.914 1.00 40.49 B 2791 CB ASP 157 14.391 4.083 53.750 1.00 40.92 B 2792 CG ASP 157 13.192 3.535 52.985 1.00 41.43 B 2793 OD1 ASP 157 12.330 2.899 53.628 1.00 41.85 B 2794 OD2 ASP 157 13.115 3.745 51.752 1.00 41.53 B 2795 C ASP 157 16.816 4.723 53.729 1.00 40.33 B 2796 O ASP 157 16.605 5.720 54.410 1.00 40.34 B 2797 N GLY 158 18.010 4.133 53.657 1.00 40.15 B 2798 CA GLY 158 19.140 4.691 54.365 1.00 39.99 B 2799 C GLY 158 19.208 4.408 55.854 1.00 40.01 B 2800 O GLY 158 19.720 5.220 56.627 1.00 39.89 B 2801 N ILE 159 18.691 3.260 56.270 1.00 39.97 B 2802 CA ILE 159 18.712 2.894 57.678 1.00 40.14 B 2803 CB ILE 159 17.291 2.866 58.288 1.00 40.25 B 2804 CG2 ILE 159 17.342 2.297 59.717 1.00 40.47 B 2805 CG1 ILE 159 16.699 4.270 58.296 1.00 40.50 B 2806 CD1 ILE 159 15.253 4.319 58.750 1.00 40.85 B 2807 C ILE 159 19.299 1.508 57.827 1.00 40.03 B 2808 O ILE 159 19.093 .652 56.974 1.00 40.19 B 2809 N LEU 160 20.043 1.298 58.906 1.00 39.83 B 2810 CA LEU 160 20.617 −.002 59.190 1.00 39.58 B 2811 CB LEU 160 22.143 .065 59.282 1.00 39.62 B 2812 CG LEU 160 22.798 −1.270 59.656 1.00 39.78 B 2813 CD1 LEU 160 22.595 −2.268 58.535 1.00 39.75 B 2814 CD2 LEU 160 24.282 −1.076 59.920 1.00 39.82 B 2815 C LEU 160 20.044 −.429 60.535 1.00 39.57 B 2816 O LEU 160 20.316 .194 61.571 1.00 39.38 B 2817 N GLY 161 19.233 −1.478 60.510 1.00 39.51 B 2818 CA GLY 161 18.649 −1.985 61.738 1.00 39.53 B 2819 C GLY 161 19.532 −3.094 62.270 1.00 39.62 B 2820 O GLY 161 19.982 −3.950 61.514 1.00 39.47 B 2821 N LEU 162 19.795 −3.075 63.570 1.00 39.77 B 2822 CA LEU 162 20.640 −4.084 64.191 1.00 39.95 B 2823 CB LEU 162 21.800 −3.412 64.926 1.00 39.98 B 2824 CG LEU 162 22.800 −2.611 64.088 1.00 39.93 B 2825 CD1 LEU 162 23.870 −2.025 65.010 1.00 39.86 B 2826 CD2 LEU 162 23.434 −3.519 63.046 1.00 39.77 B 2827 C LEU 162 19.845 −4.915 65.185 1.00 40.25 B 2828 O LEU 162 19.181 −4.371 66.061 1.00 40.06 B 2829 N SER 163 19.923 −6.232 65.047 1.00 40.73 B 2830 CA SER 163 19.225 −7.140 65.948 1.00 41.50 B 2831 CB SER 163 18.017 −7.774 65.255 1.00 41.34 B 2832 OG SER 163 17.060 −6.787 64.940 1.00 41.93 B 2833 C SER 163 20.177 −8.229 66.394 1.00 41.90 B 2834 O SER 163 21.069 −8.628 65.649 1.00 41.79 B 2835 N PHE 164 19.965 −8.708 67.613 1.00 42.62 B 2836 CA PHE 164 20.790 −9.752 68.194 1.00 43.59 B 2837 CB PHE 164 21.629 −9.164 69.325 1.00 43.10 B 2838 CG PHE 164 22.354 −7.909 68.939 1.00 42.72 B 2839 CD1 PHE 164 22.033 −6.694 69.532 1.00 42.56 B 2840 CD2 PHE 164 23.350 −7.939 67.966 1.00 42.53 B 2841 CE1 PHE 164 22.695 −5.517 69.157 1.00 42.44 B 2842 CE2 PHE 164 24.015 −6.770 67.587 1.00 42.40 B 2843 CZ PHE 164 23.684 −5.560 68.186 1.00 42.30 B 2844 C PHE 164 19.885 −10.854 68.719 1.00 44.57 B 2845 O PHE 164 18.927 −10.593 69.440 1.00 44.62 B 2846 N SER 165 20.192 −12.086 68.343 1.00 45.81 B 2847 CA SER 165 19.406 −13.237 68.756 1.00 47.07 B 2848 CB SER 165 18.740 −13.869 67.534 1.00 47.20 B 2849 OG SER 165 18.030 −15.044 67.884 1.00 47.51 B 2850 C SER 165 20.276 −14.274 69.450 1.00 48.03 B 2851 O SER 165 21.477 −14.371 69.190 1.00 47.90 B 2852 N PRO 166 19.680 −15.053 70.367 1.00 48.99 B 2853 CD PRO 166 18.371 −14.808 70.991 1.00 49.16 B 2854 CA PRO 166 20.412 −16.093 71.101 1.00 49.70 B 2855 CB PRO 166 19.505 −16.375 72.303 1.00 49.59 B 2856 CG PRO 166 18.671 −15.115 72.421 1.00 49.47 B 2857 C PRO 166 20.562 −17.302 70.183 1.00 50.32 B 2858 O PRO 166 21.460 −18.124 70.361 1.00 50.60 B 2859 N ASP 167 19.658 −17.388 69.208 1.00 51.19 B 2860 CA ASP 167 19.676 −18.454 68.210 1.00 51.86 B 2861 CB ASP 167 18.444 −19.374 68.339 1.00 52.48 B 2862 CG ASP 167 17.131 −18.684 67.994 1.00 53.04 B 2863 OD1 ASP 167 17.150 −17.538 67.483 1.00 53.48 B 2864 OD2 ASP 167 16.075 −19.309 68.238 1.00 53.42 B 2865 C ASP 167 19.739 −17.856 66.803 1.00 52.05 B 2866 O ASP 167 20.231 −16.736 66.626 1.00 52.04 B 2867 N THR 168 19.244 −18.605 65.822 1.00 52.24 B 2868 CA THR 168 19.275 −18.160 64.438 1.00 52.52 B 2869 CB THR 168 19.601 −19.338 63.460 1.00 52.70 B 2870 OG1 THR 168 18.426 −20.136 63.264 1.00 52.94 B 2871 CG2 THR 168 20.742 −20.229 63.992 1.00 52.77 B 2872 C THR 168 17.948 −17.539 64.006 1.00 52.52 B 2873 O THR 168 17.751 −17.201 62.838 1.00 52.57 B 2874 N SER 169 17.029 −17.390 64.949 1.00 52.53 B 2875 CA SER 169 15.732 −16.808 64.630 1.00 52.52 B 2876 CB SER 169 14.657 −17.285 65.624 1.00 52.63 B 2877 OG SER 169 14.862 −16.745 66.921 1.00 52.94 B 2878 C SER 169 15.855 −15.301 64.685 1.00 52.30 B 2879 O SER 169 16.604 −14.771 65.501 1.00 52.37 B 2880 N ILE 170 15.129 −14.629 63.797 1.00 52.04 B 2881 CA ILE 170 15.123 −13.170 63.699 1.00 51.76 B 2882 CB ILE 170 14.443 −12.701 62.387 1.00 51.87 B 2883 CG2 ILE 170 14.507 −11.174 62.267 1.00 51.94 B 2884 CG1 ILE 170 15.132 −13.338 61.176 1.00 52.02 B 2885 CD1 ILE 170 14.499 −12.952 59.862 1.00 52.12 B 2886 C ILE 170 14.355 −12.538 64.866 1.00 51.42 B 2887 O ILE 170 13.164 −12.793 65.032 1.00 51.55 B 2888 N PRO 171 15.021 −11.700 65.679 1.00 51.00 B 2889 CD PRO 171 16.459 −11.373 65.694 1.00 50.87 B 2890 CA PRO 171 14.330 −11.065 66.804 1.00 50.58 B 2891 CB PRO 171 15.406 −10.155 67.391 1.00 50.62 B 2892 CG PRO 171 16.660 −10.934 67.127 1.00 50.76 B 2893 C PRO 171 13.126 −10.278 66.289 1.00 50.24 B 2894 O PRO 171 13.166 −9.720 65.190 1.00 50.16 B 2895 N GLU 172 12.054 −10.237 67.074 1.00 49.84 B 2896 CA GLU 172 10.855 −9.514 66.666 1.00 49.51 B 2897 CB GLU 172 9.652 −9.909 67.540 1.00 50.12 B 2898 CG GLU 172 9.453 −9.065 68.797 1.00 51.12 B 2899 CD GLU 172 8.170 −9.422 69.548 1.00 51.84 B 2900 OE1 GLU 172 7.546 −10.461 69.213 1.00 52.26 B 2901 OE2 GLU 172 7.791 −8.667 70.477 1.00 52.28 B 2902 C GLU 172 11.103 −8.012 66.753 1.00 48.81 B 2903 O GLU 172 10.439 −7.224 66.083 1.00 48.69 B 2904 N LYS 173 12.064 −7.619 67.583 1.00 48.05 B 2905 CA LYS 173 12.407 −6.207 67.734 1.00 47.37 B 2906 CB LYS 173 12.023 −5.696 69.126 1.00 47.74 B 2907 CG LYS 173 10.515 −5.552 69.338 1.00 48.42 B 2908 CD LYS 173 10.177 −4.903 70.678 1.00 48.90 B 2909 CE LYS 173 8.668 −4.655 70.794 1.00 49.33 B 2910 NZ LYS 173 8.276 −3.907 72.038 1.00 49.77 B 2911 C LYS 173 13.896 −5.987 67.503 1.00 46.60 B 2912 O LYS 173 14.715 −6.859 67.780 1.00 46.44 B 2913 N GLU 174 14.243 −4.820 66.986 1.00 45.80 B 2914 CA GLU 174 15.640 −4.514 66.730 1.00 45.06 B 2915 CB GLU 174 15.769 −3.670 65.466 1.00 44.62 B 2916 CG GLU 174 15.225 −4.386 64.245 1.00 44.00 B 2917 CD GLU 174 15.485 −3.643 62.962 1.00 43.55 B 2918 OE1 GLU 174 14.992 −2.505 62.820 1.00 43.16 B 2919 OE2 GLU 174 16.187 −4.202 62.096 1.00 43.38 B 2920 C GLU 174 16.224 −3.795 67.924 1.00 44.73 B 2921 O GLU 174 15.503 −3.129 68.659 1.00 44.71 B 2922 N ALA 175 17.529 −3.947 68.120 1.00 44.36 B 2923 CA ALA 175 18.220 −3.322 69.242 1.00 44.03 B 2924 CB ALA 175 19.475 −4.120 69.588 1.00 43.98 B 2925 C ALA 175 18.590 −1.875 68.956 1.00 43.77 B 2926 O ALA 175 18.631 −1.046 69.863 1.00 43.58 B 2927 N ALA 176 18.866 −1.576 67.694 1.00 43.60 B 2928 CA ALA 176 19.241 −.225 67.318 1.00 43.48 B 2929 CB ALA 176 20.722 .006 67.623 1.00 43.40 B 2930 C ALA 176 18.965 .065 65.848 1.00 43.40 B 2931 O ALA 176 18.955 −.844 65.015 1.00 43.29 B 2932 N LEU 177 18.747 1.338 65.545 1.00 43.43 B 2933 CA LEU 177 18.489 1.784 64.186 1.00 43.57 B 2934 CB LEU 177 17.085 2.356 64.052 1.00 43.76 B 2935 CG LEU 177 15.951 1.368 64.264 1.00 44.08 B 2936 CD1 LEU 177 14.635 2.092 64.008 1.00 44.44 B 2937 CD2 LEU 177 16.099 .186 63.306 1.00 44.33 B 2938 C LEU 177 19.474 2.876 63.820 1.00 43.52 B 2939 O LEU 177 19.379 4.001 64.317 1.00 43.68 B 2940 N ILE 178 20.415 2.553 62.951 1.00 43.26 B 2941 CA ILE 178 21.397 3.530 62.542 1.00 42.90 B 2942 CB ILE 178 22.727 2.836 62.291 1.00 42.96 B 2943 CG2 ILE 178 23.773 3.844 61.862 1.00 42.91 B 2944 CG1 ILE 178 23.124 2.096 63.574 1.00 43.04 B 2945 CD1 ILE 178 24.397 1.325 63.482 1.00 43.38 B 2946 C ILE 178 20.878 4.248 61.301 1.00 42.70 B 2947 O ILE 178 20.779 3.662 60.226 1.00 42.77 B 2948 N GLU 179 20.516 5.513 61.471 1.00 42.39 B 2949 CA GLU 179 19.985 6.294 60.367 1.00 42.19 B 2950 CB GLU 179 18.908 7.241 60.880 1.00 42.69 B 2951 CG GLU 179 17.863 6.513 61.715 1.00 43.77 B 2952 CD GLU 179 16.730 7.415 62.146 1.00 44.44 B 2953 OE1 GLU 179 16.872 8.654 62.041 1.00 45.03 B 2954 OE2 GLU 179 15.695 6.887 62.602 1.00 45.01 B 2955 C GLU 179 21.088 7.062 59.667 1.00 41.66 B 2956 O GLU 179 21.371 8.216 59.987 1.00 41.68 B 2957 N ASN 180 21.703 6.399 58.698 1.00 40.93 B 2958 CA ASN 180 22.783 6.986 57.925 1.00 40.29 B 2959 CB ASN 180 24.087 6.933 58.731 1.00 40.39 B 2960 CG ASN 180 25.235 7.594 58.011 1.00 40.49 B 2961 OD1 ASN 180 25.828 7.016 57.103 1.00 40.54 B 2962 ND2 ASN 180 25.545 8.830 58.402 1.00 40.58 B 2963 C ASN 180 22.918 6.192 56.638 1.00 39.68 B 2964 O ASN 180 23.260 5.008 56.653 1.00 39.49 B 2965 N LYS 181 22.633 6.852 55.523 1.00 39.22 B 2966 CA LYS 181 22.679 6.212 54.212 1.00 38.74 B 2967 CB LYS 181 22.402 7.237 53.111 1.00 38.86 B 2968 CG LYS 181 22.295 6.628 51.708 1.00 38.92 B 2969 CD LYS 181 21.143 5.616 51.645 1.00 39.15 B 2970 CE LYS 181 20.789 5.244 50.202 1.00 39.22 B 2971 NZ LYS 181 19.618 4.328 50.153 1.00 39.40 B 2972 C LYS 181 23.996 5.504 53.918 1.00 38.49 B 2973 O LYS 181 24.010 4.323 53.582 1.00 38.22 B 2974 N ALA 182 25.099 6.233 54.046 1.00 38.19 B 2975 CA ALA 182 26.424 5.684 53.774 1.00 38.00 B 2976 CB ALA 182 27.494 6.760 54.011 1.00 37.96 B 2977 C ALA 182 26.723 4.456 54.613 1.00 37.86 B 2978 O ALA 182 27.195 3.448 54.099 1.00 37.94 B 2979 N VAL 183 26.455 4.541 55.910 1.00 37.80 B 2980 CA VAL 183 26.715 3.420 56.800 1.00 37.67 B 2981 CB VAL 183 26.640 3.864 58.282 1.00 37.56 B 2982 CG1 VAL 183 26.752 2.659 59.211 1.00 37.39 B 2983 CG2 VAL 183 27.782 4.847 58.575 1.00 37.59 B 2984 C VAL 183 25.746 2.265 56.556 1.00 37.73 B 2985 O VAL 183 26.120 1.094 56.687 1.00 37.63 B 2986 N SER 184 24.513 2.587 56.176 1.00 37.66 B 2987 CA SER 184 23.512 1.549 55.943 1.00 37.80 B 2988 CB SER 184 22.197 2.170 55.438 1.00 37.71 B 2989 OG SER 184 22.277 2.593 54.086 1.00 37.69 B 2990 C SER 184 23.982 .446 54.989 1.00 37.86 B 2991 O SER 184 23.620 −.718 55.162 1.00 38.03 B 2992 N SER 185 24.807 .791 54.001 1.00 37.91 B 2993 CA SER 185 25.280 −.213 53.048 1.00 38.02 B 2994 CB SER 185 25.174 .329 51.625 1.00 38.00 B 2995 OG SER 185 26.058 1.422 51.448 1.00 38.14 B 2996 C SER 185 26.715 −.682 53.281 1.00 38.13 B 2997 O SER 185 27.184 −1.611 52.618 1.00 38.15 B 2998 N ALA 186 27.410 −.051 54.221 1.00 38.18 B 2999 CA ALA 186 28.798 −.402 54.489 1.00 38.35 B 3000 CB ALA 186 29.361 .471 55.626 1.00 38.24 B 3001 C ALA 186 28.993 −1.872 54.817 1.00 38.42 B 3002 O ALA 186 29.856 −2.525 54.240 1.00 38.53 B 3003 N VAL 187 28.195 −2.394 55.740 1.00 38.61 B 3004 CA VAL 187 28.328 −3.791 56.131 1.00 38.82 B 3005 CB VAL 187 27.256 −4.194 57.167 1.00 38.75 B 3006 CG1 VAL 187 27.395 −5.670 57.513 1.00 38.72 B 3007 CG2 VAL 187 27.405 −3.348 58.420 1.00 38.82 B 3008 C VAL 187 28.257 −4.741 54.937 1.00 38.98 B 3009 O VAL 187 29.143 −5.570 54.750 1.00 38.83 B 3010 N LEU 188 27.214 −4.625 54.123 1.00 39.29 B 3011 CA LEU 188 27.088 −5.510 52.966 1.00 39.62 B 3012 CB LEU 188 25.748 −5.291 52.264 1.00 39.52 B 3013 CG LEU 188 25.445 −6.212 51.080 1.00 39.49 B 3014 CD1 LEU 188 25.559 −7.676 51.495 1.00 39.46 B 3015 CD2 LEU 188 24.064 −5.899 50.559 1.00 39.39 B 3016 C LEU 188 28.230 −5.270 51.984 1.00 39.94 B 3017 O LEU 188 28.705 −6.191 51.322 1.00 39.83 B 3018 N GLU 189 28.664 −4.020 51.894 1.00 40.45 B 3019 CA GLU 189 29.760 −3.663 51.005 1.00 41.13 B 3020 CB GLU 189 30.035 −2.161 51.094 1.00 41.24 B 3021 CG GLU 189 31.115 −1.673 50.161 1.00 41.69 B 3022 CD GLU 189 30.654 −1.591 48.721 1.00 41.85 B 3023 OE1 GLU 189 29.616 −.949 48.461 1.00 41.80 B 3024 OE2 GLU 189 31.335 −2.163 47.847 1.00 42.32 B 3025 C GLU 189 31.020 −4.440 51.389 1.00 41.41 B 3026 O GLU 189 31.725 −4.961 50.523 1.00 41.54 B 3027 N THR 190 31.303 −4.518 52.689 1.00 41.79 B 3028 CA THR 190 32.486 −5.237 53.162 1.00 42.21 B 3029 CB THR 190 32.727 −5.026 54.673 1.00 42.24 B 3030 OG1 THR 190 31.680 −5.667 55.414 1.00 42.19 B 3031 CG2 THR 190 32.762 −3.534 55.012 1.00 42.05 B 3032 C THR 190 32.354 −6.736 52.934 1.00 42.52 B 3033 O THR 190 33.318 −7.478 53.076 1.00 42.62 B 3034 N MET 191 31.159 −7.189 52.580 1.00 42.82 B 3035 CA MET 191 30.962 −8.612 52.369 1.00 43.21 B 3036 CB MET 191 29.681 −9.046 53.056 1.00 43.46 B 3037 CG MET 191 29.760 −8.921 54.551 1.00 43.97 B 3038 SD MET 191 28.164 −9.202 55.245 1.00 44.79 B 3039 CE MET 191 28.526 −8.892 56.998 1.00 44.57 B 3040 C MET 191 30.936 −9.060 50.915 1.00 43.35 B 3041 O MET 191 31.417 −10.148 50.595 1.00 43.23 B 3042 N ILE 192 30.370 −8.237 50.039 1.00 43.58 B 3043 CA ILE 192 30.291 −8.591 48.625 1.00 43.98 B 3044 CB ILE 192 28.853 −9.000 48.217 1.00 43.85 B 3045 CG2 ILE 192 28.439 −10.249 48.966 1.00 43.73 B 3046 CG1 ILE 192 27.882 −7.845 48.475 1.00 43.66 B 3047 CD1 ILE 192 26.485 −8.087 47.922 1.00 43.56 B 3048 C ILE 192 30.746 −7.470 47.701 1.00 44.41 B 3049 O ILE 192 30.623 −7.574 46.481 1.00 44.24 B 3050 N GLY 193 31.262 −6.397 48.289 1.00 45.00 B 3051 CA GLY 193 31.736 −5.276 47.501 1.00 45.90 B 3052 C GLY 193 33.059 −5.577 46.821 1.00 46.58 B 3053 O GLY 193 33.675 −6.617 47.067 1.00 46.43 B 3054 N GLU 194 33.502 −4.655 45.975 1.00 47.35 B 3055 CA GLU 194 34.749 −4.833 45.247 1.00 48.29 B 3056 CB GLU 194 35.106 −3.555 44.492 1.00 48.33 B 3057 CG GLU 194 36.206 −3.739 43.460 1.00 48.56 B 3058 CD GLU 194 36.792 −2.418 42.979 1.00 48.66 B 3059 OE1 GLU 194 36.092 −1.381 43.061 1.00 48.60 B 3060 OE2 GLU 194 37.952 −2.416 42.506 1.00 48.79 B 3061 C GLU 194 35.928 −5.208 46.144 1.00 48.92 B 3062 O GLU 194 36.695 −6.121 45.827 1.00 49.02 B 3063 N HIS 195 36.056 −4.524 47.277 1.00 49.63 B 3064 CA HIS 195 37.189 −4.764 48.166 1.00 50.42 B 3065 CB HIS 195 37.550 −3.468 48.880 1.00 50.71 B 3066 CG HIS 195 37.833 −2.346 47.937 1.00 51.19 B 3067 CD2 HIS 195 37.296 −1.103 47.823 1.00 51.39 B 3068 ND1 HIS 195 38.735 −2.459 46.894 1.00 51.39 B 3069 CE1 HIS 195 38.743 −1.339 46.193 1.00 51.51 B 3070 NE2 HIS 195 37.877 −.502 46.741 1.00 51.64 B 3071 C HIS 195 37.065 −5.914 49.144 1.00 50.80 B 3072 O HIS 195 37.977 −6.154 49.935 1.00 50.97 B 3073 N ALA 196 35.959 −6.644 49.098 1.00 51.08 B 3074 CA ALA 196 35.819 −7.795 49.978 1.00 51.47 B 3075 CB ALA 196 34.375 −8.266 50.006 1.00 51.29 B 3076 C ALA 196 36.711 −8.858 49.335 1.00 51.73 B 3077 O ALA 196 36.597 −9.105 48.133 1.00 51.89 B 3078 N VAL 197 37.599 −9.477 50.106 1.00 52.04 B 3079 CA VAL 197 38.465 −10.489 49.519 1.00 52.26 B 3080 CB VAL 197 39.826 −10.623 50.254 1.00 52.51 B 3081 CG1 VAL 197 40.691 −11.638 49.512 1.00 52.65 B 3082 CG2 VAL 197 40.556 −9.282 50.270 1.00 52.53 B 3083 C VAL 197 37.798 −11.851 49.479 1.00 52.23 B 3084 O VAL 197 37.899 −12.566 48.482 1.00 52.40 B 3085 N SER 198 37.107 −12.220 50.548 1.00 52.13 B 3086 CA SER 198 36.429 −13.513 50.553 1.00 51.95 B 3087 CB SER 198 35.740 −13.764 51.886 1.00 52.14 B 3088 OG SER 198 36.684 −13.861 52.938 1.00 52.47 B 3089 C SER 198 35.391 −13.493 49.450 1.00 51.72 B 3090 O SER 198 34.429 −12.733 49.514 1.00 51.76 B 3091 N PRO 199 35.577 −14.320 48.415 1.00 51.44 B 3092 CD PRO 199 36.784 −15.079 48.038 1.00 51.39 B 3093 CA PRO 199 34.610 −14.333 47.318 1.00 51.14 B 3094 CB PRO 199 35.457 −14.735 46.130 1.00 51.27 B 3095 CG PRO 199 36.344 −15.754 46.744 1.00 51.36 B 3096 C PRO 199 33.472 −15.299 47.473 1.00 50.85 B 3097 O PRO 199 32.655 −15.381 46.564 1.00 50.87 B 3098 N ASP 200 33.399 −16.015 48.594 1.00 50.39 B 3099 CA ASP 200 32.351 −17.017 48.767 1.00 49.97 B 3100 CB ASP 200 32.499 −17.761 50.123 1.00 50.08 B 3101 CG ASP 200 32.358 −16.837 51.338 1.00 50.18 B 3102 OD1 ASP 200 32.336 −15.598 51.174 1.00 50.31 B 3103 OD2 ASP 200 32.279 −17.357 52.479 1.00 50.28 B 3104 C ASP 200 30.925 −16.488 48.590 1.00 49.64 B 3105 O ASP 200 30.109 −17.110 47.898 1.00 49.46 B 3106 N LEU 201 30.613 −15.346 49.188 1.00 49.24 B 3107 CA LEU 201 29.267 −14.804 49.061 1.00 49.02 B 3108 CB LEU 201 29.046 −13.648 50.044 1.00 49.14 B 3109 CG LEU 201 28.857 −14.062 51.513 1.00 49.23 B 3110 CD1 LEU 201 28.846 −12.833 52.390 1.00 49.11 B 3111 CD2 LEU 201 27.558 −14.833 51.680 1.00 49.22 B 3112 C LEU 201 29.010 −14.351 47.632 1.00 48.81 B 3113 O LEU 201 27.945 −14.612 47.086 1.00 48.56 B 3114 N LYS 202 29.994 −13.699 47.021 1.00 48.72 B 3115 CA LYS 202 29.847 −13.225 45.648 1.00 48.73 B 3116 CB LYS 202 31.106 −12.493 45.195 1.00 48.87 B 3117 CG LYS 202 31.407 −11.242 45.979 1.00 49.17 B 3118 CD LYS 202 32.650 −10.580 45.431 1.00 49.64 B 3119 CE LYS 202 33.209 −9.574 46.415 1.00 50.07 B 3120 NZ LYS 202 34.703 −9.507 46.342 1.00 50.51 B 3121 C LYS 202 29.564 −14.385 44.706 1.00 48.61 B 3122 O LYS 202 28.737 −14.277 43.804 1.00 48.42 B 3123 N ARG 203 30.250 −15.503 44.926 1.00 48.60 B 3124 CA ARG 203 30.058 −16.684 44.094 1.00 48.66 B 3125 CB ARG 203 31.087 −17.753 44.450 1.00 49.17 B 3126 CG ARG 203 32.489 −17.349 44.052 1.00 49.89 B 3127 CD ARG 203 33.531 −18.353 44.501 1.00 50.55 B 3128 NE ARG 203 34.872 −17.859 44.202 1.00 51.37 B 3129 CZ ARG 203 35.996 −18.463 44.578 1.00 51.84 B 3130 NH1 ARG 203 35.945 −19.596 45.274 1.00 52.02 B 3131 NH2 ARG 203 37.174 −17.931 44.263 1.00 52.02 B 3132 C ARG 203 28.654 −17.242 44.229 1.00 48.40 B 3133 O ARG 203 28.025 −17.598 43.229 1.00 48.32 B 3134 N CYS 204 28.155 −17.316 45.461 1.00 48.04 B 3135 CA CYS 204 26.803 −17.819 45.677 1.00 47.72 B 3136 CB CYS 204 26.424 −17.794 47.161 1.00 47.90 B 3137 SG CYS 204 27.254 −19.022 48.186 1.00 48.49 B 3138 C CYS 204 25.828 −16.949 44.911 1.00 47.34 B 3139 O CYS 204 24.968 −17.452 44.206 1.00 47.26 B 3140 N LEU 205 25.969 −15.636 45.057 1.00 46.97 B 3141 CA LEU 205 25.089 −14.698 44.382 1.00 46.69 B 3142 CB LEU 205 25.493 −13.267 44.742 1.00 46.40 B 3143 CG LEU 205 25.144 −12.876 46.184 1.00 46.24 B 3144 CD1 LEU 205 25.849 −11.584 46.574 1.00 45.98 B 3145 CD2 LEU 205 23.631 −12.735 46.309 1.00 45.95 B 3146 C LEU 205 25.091 −14.898 42.867 1.00 46.64 B 3147 O LEU 205 24.035 −14.908 42.236 1.00 46.55 B 3148 N ALA 206 26.277 −15.070 42.294 1.00 46.69 B 3149 CA ALA 206 26.413 −15.278 40.855 1.00 46.88 B 3150 CB ALA 206 27.890 −15.249 40.453 1.00 46.76 B 3151 C ALA 206 25.789 −16.608 40.449 1.00 47.02 B 3152 O ALA 206 25.157 −16.712 39.401 1.00 47.02 B 3153 N ALA 207 25.950 −17.615 41.299 1.00 47.19 B 3154 CA ALA 207 25.420 −18.944 41.024 1.00 47.39 B 3155 CB ALA 207 26.029 −19.947 42.001 1.00 47.39 B 3156 C ALA 207 23.898 −19.048 41.073 1.00 47.64 B 3157 O ALA 207 23.280 −19.643 40.189 1.00 47.61 B 3158 N ARG 208 23.285 −18.456 42.089 1.00 47.89 B 3159 CA ARG 208 21.840 −18.568 42.240 1.00 48.31 B 3160 CB ARG 208 21.515 −18.804 43.723 1.00 48.48 B 3161 CG ARG 208 22.580 −18.279 44.667 1.00 48.69 B 3162 CD ARG 208 22.741 −19.152 45.909 1.00 48.67 B 3163 NE ARG 208 21.526 −19.153 46.710 1.00 48.74 B 3164 CZ ARG 208 21.111 −20.176 47.448 1.00 48.57 B 3165 NH1 ARG 208 21.812 −21.300 47.504 1.00 48.42 B 3166 NH2 ARG 208 19.973 −20.072 48.114 1.00 48.59 B 3167 C ARG 208 20.930 −17.482 41.668 1.00 48.49 B 3168 O ARG 208 19.725 −17.699 41.540 1.00 48.40 B 3169 N LEU 209 21.476 −16.325 41.312 1.00 48.80 B 3170 CA LEU 209 20.622 −15.272 40.768 1.00 49.22 B 3171 CB LEU 209 21.320 −13.909 40.848 1.00 49.09 B 3172 CG LEU 209 20.906 −13.011 42.022 1.00 49.04 B 3173 CD1 LEU 209 19.405 −12.750 41.957 1.00 48.97 B 3174 CD2 LEU 209 21.263 −13.669 43.337 1.00 48.92 B 3175 C LEU 209 20.123 −15.500 39.338 1.00 49.67 B 3176 O LEU 209 18.976 −15.190 39.025 1.00 49.50 B 3177 N PRO 210 20.971 −16.046 38.452 1.00 50.19 B 3178 CD PRO 210 22.389 −16.414 38.618 1.00 50.27 B 3179 CA PRO 210 20.533 −16.273 37.070 1.00 50.82 B 3180 CB PRO 210 21.692 −17.062 36.472 1.00 50.64 B 3181 CG PRO 210 22.879 −16.463 37.178 1.00 50.46 B 3182 C PRO 210 19.194 −16.996 36.952 1.00 51.51 B 3183 O PRO 210 18.291 −16.530 36.258 1.00 51.48 B 3184 N ALA 211 19.064 −18.122 37.645 1.00 52.30 B 3185 CA ALA 211 17.833 −18.895 37.604 1.00 53.24 B 3186 CB ALA 211 17.960 −20.130 38.485 1.00 53.25 B 3187 C ALA 211 16.635 −18.062 38.037 1.00 53.94 B 3188 O ALA 211 15.554 −18.190 37.465 1.00 53.95 B 3189 N LEU 212 16.818 −17.211 39.045 1.00 54.79 B 3190 CA LEU 212 15.722 −16.363 39.512 1.00 55.73 B 3191 CB LEU 212 16.049 −15.749 40.875 1.00 55.73 B 3192 CG LEU 212 16.141 −16.680 42.083 1.00 55.92 B 3193 CD1 LEU 212 16.463 −15.855 43.322 1.00 55.87 B 3194 CD2 LEU 212 14.822 −17.431 42.271 1.00 55.95 B 3195 C LEU 212 15.420 −15.238 38.523 1.00 56.42 B 3196 O LEU 212 14.264 −14.901 38.286 1.00 56.37 B 3197 N LEU 213 16.465 −14.659 37.943 1.00 57.37 B 3198 CA LEU 213 16.291 −13.562 37.000 1.00 58.47 B 3199 CB LEU 213 17.636 −12.897 36.713 1.00 58.27 B 3200 CG LEU 213 18.338 −12.286 37.926 1.00 58.28 B 3201 CD1 LEU 213 19.683 −11.738 37.498 1.00 58.29 B 3202 CD2 LEU 213 17.474 −11.191 38.534 1.00 58.19 B 3203 C LEU 213 15.650 −13.999 35.687 1.00 59.34 B 3204 O LEU 213 14.823 −13.276 35.124 1.00 59.41 B 3205 N ASN 214 16.027 −15.180 35.205 1.00 60.39 B 3206 CA ASN 214 15.492 −15.684 33.943 1.00 61.55 B 3207 CB ASN 214 16.411 −16.765 33.357 1.00 61.91 B 3208 CG ASN 214 16.403 −18.053 34.170 1.00 62.38 B 3209 OD1 ASN 214 15.530 −18.262 35.017 1.00 62.69 B 3210 ND2 ASN 214 17.372 −18.936 33.899 1.00 62.65 B 3211 C ASN 214 14.072 −16.233 34.067 1.00 62.15 B 3212 O ASN 214 13.566 −16.860 33.134 1.00 62.30 B 3213 N GLU 215 13.438 −15.999 35.213 1.00 62.82 B 3214 CA GLU 215 12.071 −16.465 35.443 1.00 63.51 B 3215 CB GLU 215 11.780 −16.547 36.942 1.00 63.81 B 3216 CG GLU 215 11.453 −15.201 37.585 1.00 64.40 B 3217 CD GLU 215 11.472 −15.263 39.107 1.00 64.72 B 3218 OE1 GLU 215 11.573 −16.381 39.661 1.00 64.95 B 3219 OE2 GLU 215 11.383 −14.193 39.751 1.00 64.97 B 3220 C GLU 215 11.099 −15.479 34.800 1.00 63.76 B 3221 OT1 GLU 215 11.556 −14.377 34.424 1.00 63.97 B 3222 OT2 GLU 215 9.899 −15.810 34.682 1.00 63.98 B 3223 OH2 WAT 1 31.093 −4.250 43.359 1.00 38.31 W 3224 OH2 WAT 2 22.205 −3.369 72.055 1.00 41.07 W 3225 OH2 WAT 3 20.554 −.944 41.661 1.00 39.45 W 3226 OH2 WAT 4 17.896 −6.055 62.376 1.00 38.35 W 3227 OH2 WAT 5 20.405 21.269 30.480 1.00 36.21 W 3228 OH2 WAT 6 12.876 −1.564 64.212 1.00 45.53 W 3229 OH2 WAT 7 13.804 3.554 27.585 1.00 43.05 W 3230 OH2 WAT 8 24.786 −3.380 54.771 1.00 35.11 W 3231 OH2 WAT 9 28.066 1.015 49.442 1.00 45.06 W 3232 OH2 WAT 10 28.942 .733 38.701 1.00 34.28 W 3233 OH2 WAT 11 11.034 1.040 35.900 1.00 62.48 W 3234 OH2 WAT 12 11.958 −2.453 50.194 1.00 45.87 W 3235 OH2 WAT 13 21.729 10.816 38.274 1.00 38.90 W 3236 OH2 WAT 14 14.717 1.042 31.574 1.00 54.49 W 3237 OH2 WAT 15 17.148 18.726 21.425 1.00 43.77 W 3238 OH2 WAT 16 14.258 −8.167 59.218 1.00 38.95 W 3239 OH2 WAT 17 25.220 14.836 50.255 1.00 39.68 W 3240 OH2 WAT 18 31.999 −6.768 44.244 1.00 36.85 W 3241 OH2 WAT 19 18.759 −3.066 41.285 1.00 36.91 W 3242 OH2 WAT 20 33.825 −.369 44.325 1.00 46.84 W 3243 OH2 WAT 21 21.027 6.946 63.895 1.00 39.53 W 3244 OH2 WAT 22 26.841 26.528 37.222 1.00 41.75 W 3245 OH2 WAT 23 25.367 9.122 54.856 1.00 37.37 W 3246 OH2 WAT 24 25.067 .794 29.176 1.00 43.46 W 3247 OH2 WAT 25 19.710 −3.614 38.582 1.00 41.87 W 3248 OH2 WAT 26 17.814 2.392 46.303 1.00 43.24 W 3249 OH2 WAT 27 25.147 24.525 18.999 1.00 37.60 W 3250 OH2 WAT 28 27.097 13.442 48.534 1.00 41.43 W 3251 OH2 WAT 29 27.483 37.303 38.185 1.00 49.70 W 3252 OH2 WAT 30 29.357 14.737 45.872 1.00 46.90 W 3253 OH2 WAT 31 17.807 −7.527 69.022 1.00 44.13 W 3254 OH2 WAT 32 21.345 −13.823 34.901 1.00 44.32 W 3255 OH2 WAT 33 35.351 −17.312 50.704 1.00 55.78 W 3256 OH2 WAT 34 26.136 26.351 20.833 1.00 40.13 W 3257 OH2 WAT 35 32.708 −13.771 75.135 1.00 43.56 W 3258 OH2 WAT 36 12.775 2.758 37.403 1.00 45.67 W 3259 OH2 WAT 37 25.576 21.447 40.719 1.00 44.80 W 3260 OH2 WAT 38 22.179 22.412 44.230 1.00 40.57 W 3261 OH2 WAT 39 27.629 1.078 29.037 1.00 46.71 W 3262 OH2 WAT 40 15.214 −8.497 63.801 1.00 38.34 W 3263 OH2 WAT 41 33.570 −1.687 70.758 1.00 40.60 W 3264 OH2 WAT 42 31.914 −2.489 45.115 1.00 43.00 W 3265 OH2 WAT 43 23.695 2.255 70.078 1.00 43.19 W 3266 OH2 WAT 44 29.791 12.761 49.741 1.00 48.56 W 3267 OH2 WAT 45 15.071 9.940 29.979 1.00 40.83 W 3268 OH2 WAT 46 6.237 −10.540 53.081 1.00 48.79 W 3269 OH2 WAT 47 20.476 3.837 40.323 1.00 42.14 W 3270 OH2 WAT 48 29.765 5.450 42.949 1.00 41.40 W 3271 OH2 WAT 49 23.422 10.111 60.106 1.00 41.64 W 3272 OH2 WAT 50 20.860 .481 49.642 1.00 46.53 W 3273 OH2 WAT 51 5.256 8.767 49.027 1.00 55.74 W 3274 OH2 WAT 52 24.018 33.664 24.223 1.00 52.13 W 3275 OH2 WAT 53 21.760 30.910 22.406 1.00 47.05 W 3276 OH2 WAT 54 19.585 14.021 16.441 1.00 56.45 W 3277 OH2 WAT 55 20.975 −19.597 38.847 1.00 49.49 W 3278 OH2 WAT 56 13.251 1.391 60.383 1.00 54.19 W 3279 OH2 WAT 57 23.704 7.874 64.123 1.00 44.28 W 3280 OH2 WAT 58 15.256 7.236 51.233 1.00 43.50 W 3281 OH2 WAT 59 24.722 14.018 57.391 1.00 45.21 W 3282 OH2 WAT 60 26.451 .059 45.352 1.00 44.50 W 3283 OH2 WAT 61 34.911 7.400 28.623 1.00 49.87 W 3284 OH2 WAT 62 16.024 −8.090 61.241 1.00 39.36 W 3285 OH2 WAT 63 24.783 9.796 62.406 1.00 46.71 W 3286 OH2 WAT 64 31.166 −2.930 69.992 1.00 41.41 W 3287 OH2 WAT 65 10.893 −9.636 41.973 1.00 44.07 W 3288 OH2 WAT 66 28.314 −12.912 62.930 1.00 41.86 W 3289 OH2 WAT 67 24.853 17.293 49.467 1.00 38.69 W 3290 OH2 WAT 68 36.526 .983 63.657 1.00 46.65 W 3291 OH2 WAT 69 18.777 3.199 43.897 1.00 57.05 W 3292 OH2 WAT 70 28.000 −.909 33.105 1.00 44.17 W 3293 OH2 WAT 71 24.106 9.098 47.740 1.00 55.73 W 3294 OH2 WAT 72 17.808 6.338 50.880 1.00 39.96 W 3295 OH2 WAT 73 36.807 14.820 35.205 1.00 49.63 W 3296 OH2 WAT 74 14.829 11.241 23.393 1.00 43.87 W 3297 OH2 WAT 75 36.031 33.971 37.266 1.00 56.30 W 3298 OH2 WAT 76 4.952 −6.504 59.504 1.00 57.63 W 3299 OH2 WAT 77 22.846 27.968 42.941 1.00 52.34 W 3300 OH2 WAT 78 12.146 −11.809 69.643 1.00 54.90 W 3301 OH2 WAT 79 19.700 5.591 42.910 1.00 51.71 W 3302 OH2 WAT 80 15.474 .949 68.278 1.00 66.40 W 3303 OH2 WAT 81 34.987 13.359 30.852 1.00 42.96 W 3304 OH2 WAT 82 38.932 7.300 62.259 1.00 63.71 W 3305 OH2 WAT 83 35.300 12.120 60.726 1.00 66.45 W 3306 OH2 WAT 84 8.372 12.069 21.462 1.00 64.68 W 3307 OH2 WAT 85 35.004 −3.331 69.181 1.00 47.28 W 3308 OH2 WAT 86 16.178 −17.345 60.213 1.00 62.52 W 3309 OH2 WAT 87 32.218 −1.490 37.454 1.00 45.67 W 3310 OH2 WAT 88 33.650 −5.544 36.673 1.00 48.90 W 3311 OH2 WAT 89 10.839 3.447 41.407 1.00 44.17 W 3312 OH2 WAT 90 15.338 8.207 53.876 1.00 45.01 W 3313 OH2 WAT 91 30.982 −3.939 36.099 1.00 38.73 W 3314 OH2 WAT 92 28.437 −19.091 76.433 1.00 48.06 W 3315 OH2 WAT 93 29.317 −3.476 34.057 1.00 49.49 W 3316 OH2 WAT 94 27.684 10.298 48.858 1.00 55.52 W 3317 OH2 WAT 95 14.673 −23.662 53.251 1.00 49.20 W 3318 OH2 WAT 96 17.556 7.948 19.460 1.00 63.81 W 3319 OH2 WAT 97 28.042 7.556 41.706 1.00 43.72 W 3320 OH2 WAT 98 16.210 26.298 51.998 1.00 60.02 W 3321 OH2 WAT 99 23.180 12.765 59.454 1.00 48.47 W 3322 OH2 WAT 100 24.091 26.235 51.196 1.00 66.16 W 3323 OH2 WAT 101 23.826 8.978 66.633 1.00 56.80 W 3324 OH2 WAT 102 3.301 13.799 45.653 1.00 66.31 W 3325 OH2 WAT 103 33.824 9.701 27.099 1.00 60.54 W 3326 OH2 WAT 104 29.786 12.544 55.054 1.00 41.18 W 3327 OH2 WAT 105 23.227 −12.967 71.600 1.00 51.29 W 3328 OH2 WAT 106 26.114 16.990 57.406 1.00 52.43 W 3329 OH2 WAT 107 25.488 27.629 39.671 1.00 50.05 W 3330 OH2 WAT 108 22.470 30.831 40.093 1.00 57.56 W 3331 OH2 WAT 109 37.775 5.213 63.399 1.00 69.73 W 3332 OH2 WAT 110 34.301 −.031 38.944 1.00 45.56 W 3333 OH2 WAT 111 27.597 2.887 47.690 1.00 60.49 W 3334 OH2 WAT 112 17.992 3.627 67.907 1.00 58.51 W 3335 OH2 WAT 113 34.212 −2.513 48.565 1.00 47.94 W 3336 OH2 WAT 114 9.142 3.223 51.976 1.00 57.69 W 3337 OH2 WAT 115 19.903 1.345 25.038 1.00 68.54 W 3338 OH2 WAT 116 20.188 2.209 52.296 1.00 42.73 W 3339 OH2 WAT 117 28.947 5.592 51.018 1.00 40.39 W 3340 OH2 WAT 118 16.572 −11.398 70.607 1.00 46.52 W 3341 OH2 WAT 119 22.371 28.957 16.258 1.00 55.29 W 3342 OH2 WAT 120 20.120 12.380 14.024 1.00 58.21 W 3343 OH2 WAT 121 30.963 2.318 25.429 1.00 48.38 W 3344 OH2 WAT 122 21.073 3.484 45.639 1.00 56.45 W 3345 OH2 WAT 123 34.100 .809 70.341 1.00 50.51 W 3346 OH2 WAT 124 18.016 −1.735 72.545 1.00 53.41 W 3347 OH2 WAT 125 32.760 17.849 19.769 1.00 51.60 W 3348 OH2 WAT 126 20.014 35.120 27.688 1.00 68.27 W 3349 OH2 WAT 127 39.302 .999 59.401 1.00 41.72 W 3350 OH2 WAT 128 33.457 4.342 66.754 1.00 67.39 W 3351 OH2 WAT 129 11.112 −.382 62.500 1.00 67.86 W 3352 OH2 WAT 130 29.176 −20.293 78.691 1.00 51.06 W 3353 OH2 WAT 131 18.735 27.403 17.177 1.00 47.80 W 3354 OH2 WAT 132 32.904 20.389 23.167 1.00 56.27 W 3355 OH2 WAT 133 9.835 −4.472 65.449 1.00 53.12 W 3356 OH2 WAT 134 32.597 28.207 35.870 1.00 55.11 W 3357 OH2 WAT 135 29.969 −25.969 56.239 1.00 48.12 W 3358 OH2 WAT 136 36.964 −1.362 65.077 1.00 44.08 W 3359 OH2 WAT 137 10.433 10.253 21.603 1.00 54.93 W 3360 OH2 WAT 138 38.129 13.412 41.162 1.00 48.39 W 3361 OH2 WAT 139 36.704 17.146 29.103 1.00 59.58 W 3362 OH2 WAT 140 27.851 −23.129 66.111 1.00 60.12 W 3363 OH2 WAT 141 34.360 13.181 19.409 1.00 66.62 W 3364 OH2 WAT 142 20.706 −23.727 62.602 1.00 54.01 W 3365 OH2 WAT 143 39.554 2.841 34.406 1.00 68.29 W 3366 OH2 WAT 144 25.204 −19.729 34.272 1.00 57.76 W 3367 OH2 WAT 145 41.086 −23.712 68.027 1.00 72.43 W 3368 OH2 WAT 146 16.943 6.274 41.247 1.00 41.20 W 3369 OH2 WAT 147 11.542 −4.401 42.425 1.00 47.73 W 3370 OH2 WAT 148 14.946 27.656 20.304 1.00 52.17 W 3371 OH2 WAT 149 24.832 5.955 23.125 1.00 48.56 W 3372 OH2 WAT 150 30.653 9.001 16.618 1.00 66.87 W 3373 OH2 WAT 151 28.998 14.078 23.475 1.00 43.35 W 3374 OH2 WAT 152 34.368 11.875 54.060 1.00 53.46 W 3375 OH2 WAT 153 25.939 8.771 17.733 1.00 69.63 W 3376 OH2 WAT 154 31.613 13.875 44.688 1.00 60.00 W 3377 OH2 WAT 155 29.255 .100 30.971 1.00 49.76 W 3378 OH2 WAT 156 19.059 29.293 41.016 1.00 55.35 W 3379 OH2 WAT 157 36.595 −7.763 43.708 1.00 56.53 W 3380 OH2 WAT 158 20.748 −5.549 73.212 1.00 58.80 W 3381 OH2 WAT 159 38.071 −6.743 71.037 1.00 56.27 W 3382 OH2 WAT 160 11.224 17.579 57.161 1.00 48.48 W 3383 OH2 WAT 161 31.397 14.497 22.933 1.00 49.77 W 3384 OH2 WAT 162 35.502 −7.801 38.951 1.00 50.71 W 3385 OH2 WAT 163 33.161 −21.147 71.386 1.00 51.02 W 3386 OH2 WAT 164 20.286 11.119 59.449 1.00 52.24 W 3387 OH2 WAT 165 34.529 24.258 33.196 1.00 67.98 W 3388 OH2 WAT 166 12.012 4.516 25.773 1.00 50.14 W 3389 OH2 WAT 167 31.772 11.810 47.996 1.00 67.99 W 3390 OH2 WAT 168 14.912 8.442 20.411 1.00 74.18 W 3391 OH2 WAT 169 9.368 26.392 46.096 1.00 63.81 W 3392 OH2 WAT 170 28.509 2.982 51.791 1.00 46.67 W 3393 OH2 WAT 171 4.996 6.432 40.740 1.00 63.03 W 3394 OH2 WAT 172 11.588 10.669 28.048 1.00 46.74 W 3395 OH2 WAT 173 14.227 23.192 18.948 1.00 49.28 W 3396 OH2 WAT 174 18.719 11.671 18.495 1.00 71.10 W 3397 OH2 WAT 175 13.190 −20.042 67.678 1.00 58.59 W 3398 OH2 WAT 176 25.777 −23.959 67.840 1.00 62.17 W 3399 OH2 WAT 177 16.999 27.742 45.551 1.00 58.42 W 3400 OH2 WAT 178 22.249 .128 71.871 1.00 65.44 W 3401 OH2 WAT 179 35.826 −4.408 52.580 1.00 58.54 W 3402 OH2 WAT 180 25.839 .223 74.936 1.00 55.69 W 3403 OH2 WAT 181 22.433 4.944 43.941 1.00 60.42 W 3404 OH2 WAT 182 29.223 −12.148 60.548 1.00 59.86 W 3405 OH2 WAT 183 15.667 16.612 20.418 1.00 49.49 W 3406 OH2 WAT 184 24.783 −21.882 46.145 1.00 68.71 W 3407 OH2 WAT 185 25.242 19.671 50.499 1.00 44.24 W 3408 OH2 WAT 186 2.423 26.673 41.340 1.00 67.24 W 3409 OH2 WAT 187 23.280 17.623 60.422 1.00 62.91 W 3410 OH2 WAT 188 15.145 32.923 37.151 1.00 65.04 W 3411 OH2 WAT 189 20.969 10.269 20.754 1.00 52.89 W 3412 OH2 WAT 190 18.175 −17.048 58.331 1.00 53.26 W 3413 OH2 WAT 191 24.571 −26.567 52.275 1.00 58.98 W 3414 OH2 WAT 192 38.246 −9.005 57.246 1.00 61.24 W 3415 OH2 WAT 193 36.305 −11.762 46.051 1.00 63.32 W 3416 OH2 WAT 194 11.497 20.108 16.174 1.00 63.58 W 3417 OH2 WAT 195 31.584 −21.544 74.117 1.00 68.96 W 3418 OH2 WAT 196 12.043 −.744 48.184 1.00 52.26 W 3419 OH2 WAT 197 11.989 14.143 21.333 1.00 61.32 W 3420 OH2 WAT 198 12.839 1.264 29.315 1.00 69.48 W 3421 OH2 WAT 199 11.860 −15.478 45.332 1.00 65.32 W 3422 OH2 WAT 200 20.430 13.555 61.068 1.00 59.82 W 3423 OH2 WAT 201 23.643 −4.606 32.061 1.00 64.48 W 3424 OH2 WAT 202 38.517 −25.787 70.646 1.00 76.00 W 3425 OH2 WAT 203 15.297 31.145 28.851 1.00 66.25 W 3426 OH2 WAT 204 15.159 2.605 25.487 1.00 60.04 W 3427 OH2 WAT 205 28.077 23.607 35.404 1.00 67.09 W 3428 OH2 WAT 206 32.761 39.897 39.324 1.00 57.67 W 3429 OH2 WAT 207 36.641 −2.074 53.768 1.00 57.82 W 3430 OH2 WAT 208 34.353 −1.946 73.339 1.00 50.05 W 3431 OH2 WAT 209 27.589 2.824 43.260 1.00 70.02 W 3432 OH2 WAT 210 12.853 −.417 41.865 1.00 57.86 W 3433 OH2 WAT 211 26.187 23.776 48.114 1.00 57.27 W 3434 OH2 WAT 212 11.985 −1.710 44.211 1.00 51.14 W 3435 OH2 WAT 213 38.689 7.218 30.912 1.00 68.27 W 3436 OH2 WAT 214 8.583 26.431 29.422 1.00 65.31 W 3437 OH2 WAT 215 17.594 15.705 17.887 1.00 54.42 W 3438 OH2 WAT 216 1.849 20.472 37.884 1.00 57.12 W 3439 OH2 WAT 217 8.333 −8.098 42.298 1.00 62.17 W 3440 OH2 WAT 218 8.946 −.483 52.167 1.00 57.91 W 3441 OH2 WAT 219 29.333 −23.629 74.187 1.00 70.25 W 3442 OH2 WAT 220 6.604 −3.624 52.392 1.00 62.34 W 3443 OH2 WAT 221 12.983 25.059 21.917 1.00 53.69 W 3444 OH2 WAT 222 38.735 −18.849 48.176 1.00 64.01 W 3445 OH2 WAT 223 8.728 −2.184 62.901 1.00 65.88 W 3446 OH2 WAT 224 8.411 4.504 49.068 1.00 60.02 W 3447 OH2 WAT 225 31.938 15.968 55.305 1.00 58.81 W 3448 OH2 WAT 226 32.527 −20.621 52.265 1.00 60.11 W 3449 OH2 WAT 227 9.073 30.520 40.192 1.00 59.71 W 3450 OH2 WAT 228 20.976 8.564 67.698 1.00 67.06 W 3451 OH2 WAT 229 40.435 −5.021 47.043 1.00 69.13 W 3452 OH2 WAT 230 11.670 −2.733 39.421 1.00 59.51 W 3453 OH2 WAT 231 33.789 14.958 43.047 1.00 67.65 W 3454 OH2 WAT 232 35.687 3.313 26.142 1.00 74.71 W 3455 OH2 WAT 233 38.617 1.882 62.137 1.00 66.43 W 3456 OH2 WAT 234 16.871 −20.946 65.437 1.00 60.62 W 3457 OH2 WAT 235 7.222 21.869 30.683 1.00 71.14 W 3458 OH2 WAT 236 29.336 18.254 60.245 1.00 72.61 W 3459 OH2 WAT 237 5.178 1.864 39.450 1.00 60.41 W 3460 OH2 WAT 238 12.637 1.590 57.377 1.00 69.21 W 3461 OH2 WAT 239 38.338 13.267 36.482 1.00 50.89 W 3462 OH2 WAT 240 19.406 −4.325 29.852 1.00 63.56 W 3463 OH2 WAT 241 15.305 −4.423 71.898 1.00 67.37 W 3464 OH2 WAT 242 11.386 −15.025 65.042 1.00 67.69 W 3465 OH2 WAT 243 24.769 3.511 50.789 1.00 54.60 W 3466 OH2 WAT 244 8.493 −8.294 50.615 1.00 58.19 W 3467 OH2 WAT 245 34.390 2.967 64.355 1.00 70.20 W 3468 OH2 WAT 246 36.585 8.991 63.426 1.00 64.27 W 3469 OH2 WAT 247 28.778 −21.201 45.284 1.00 66.53 W 3470 OH2 WAT 248 19.928 29.712 46.272 1.00 68.79 W 3471 OH2 WAT 249 36.168 −15.643 42.609 1.00 62.80 W 3472 OH2 WAT 250 6.443 29.483 39.025 1.00 71.20 W 3473 OH2 WAT 251 14.585 1.334 34.064 1.00 64.66 W 3474 OH2 WAT 252 37.851 −23.772 62.225 1.00 71.61 W 3475 OH2 WAT 253 13.134 10.148 21.360 1.00 70.24 W 3476 OH2 WAT 254 30.268 22.816 36.964 1.00 51.51 W 3477 OH2 WAT 255 37.927 3.391 40.343 1.00 57.64 W 3478 OH2 WAT 256 42.938 10.339 36.942 1.00 66.82 W 3479 OH2 WAT 257 28.860 7.512 45.386 1.00 63.93 W 3480 OH2 WAT 258 24.155 4.617 71.176 1.00 64.96 W 3481 OH2 WAT 259 13.549 7.501 55.948 1.00 53.90 W 3482 OH2 WAT 260 12.203 −3.194 66.196 1.00 45.03 W 3483 OH2 WAT 261 39.578 9.149 32.471 1.00 64.60 W 3484 OH2 WAT 262 25.827 6.707 70.171 1.00 63.75 W 3485 OH2 WAT 263 13.063 −9.369 70.044 1.00 61.85 W 3486 OH2 WAT 264 22.769 38.693 34.425 1.00 69.39 W 3487 OH2 WAT 265 24.833 4.824 42.490 1.00 46.49 W 3488 OH2 WAT 266 25.434 32.148 40.949 1.00 70.08 W 3489 OH2 WAT 267 17.356 3.009 24.217 1.00 66.40 W 3490 OH2 WAT 268 33.379 16.174 58.540 1.00 69.39 W 3491 OH2 WAT 269 28.851 −.908 45.949 1.00 46.04 W 3492 OH2 WAT 270 14.126 −.572 35.803 1.00 64.61 W 3493 OH2 WAT 271 18.950 27.610 56.135 1.00 66.68 W 3494 OH2 WAT 272 23.906 6.480 20.580 1.00 63.73 W 3495 OH2 WAT 273 33.719 −8.571 43.438 1.00 51.28 W 3496 OH2 WAT 274 24.311 26.011 16.450 1.00 43.15 W 3497 OH2 WAT 275 21.426 20.152 32.573 1.00 47.14 W 3498 OH2 WAT 276 26.446 8.758 44.029 1.00 51.61 W 3499 OH2 WAT 277 12.889 −21.632 53.500 1.00 52.81 W 3500 OH2 WAT 278 41.069 38.032 31.898 1.00 57.66 W 3501 OH2 WAT 279 23.117 28.163 40.325 1.00 44.59 W 3502 OH2 WAT 280 26.857 12.778 56.394 1.00 49.45 W 3503 OH2 WAT 281 30.368 17.578 41.493 1.00 55.61 W 3504 OH2 WAT 282 13.016 29.422 25.555 1.00 48.14 W 3505 OH2 WAT 283 19.874 29.181 52.014 1.00 71.41 W 3506 OH2 WAT 284 28.920 16.418 43.716 1.00 51.39 W 3507 OH2 WAT 285 18.685 1.850 48.511 1.00 51.50 W 3508 OH2 WAT 286 29.129 25.983 19.126 1.00 57.44 W 3509 OH2 WAT 287 13.978 25.840 18.608 1.00 60.66 W 3510 OH2 WAT 288 33.677 −18.113 32.020 1.00 60.74 W 3511 OH2 WAT 289 22.914 −20.293 70.652 1.00 58.51 W 3512 OH2 WAT 290 31.910 −12.638 49.166 1.00 53.02 W 3513 OH2 WAT 291 27.439 24.079 17.763 1.00 49.94 W 3514 OH2 WAT 292 32.424 16.265 40.423 1.00 49.57 W 3515 OH2 WAT 293 21.240 −8.372 30.296 1.00 63.65 W 3516 OH2 WAT 294 11.765 −10.836 37.034 1.00 71.61 W 3517 OH2 WAT 295 40.879 5.315 51.721 1.00 61.78 W 3518 OH2 WAT 296 2.507 23.113 38.112 1.00 60.11 W 3519 OH2 WAT 297 11.474 1.699 43.768 1.00 55.91 W 3520 OH2 WAT 298 13.539 .130 66.634 1.00 59.35 W 3521 OH2 WAT 299 41.707 2.695 55.851 1.00 53.29 W 3522 OH2 WAT 300 18.341 −15.413 75.839 1.00 63.84 W 3523 OH2 WAT 301 12.349 10.624 30.772 1.00 57.13 W 3524 OH2 WAT 302 10.595 2.398 47.881 1.00 62.67 W 3525 OH2 WAT 303 40.012 3.605 58.475 1.00 64.07 W 3526 OH2 WAT 304 18.383 −20.177 41.953 1.00 68.55 W 3527 OH2 WAT 305 21.609 30.526 44.140 1.00 74.34 W 3528 OH2 WAT 306 14.691 28.352 47.650 1.00 70.27 W 3529 OH2 WAT 307 33.449 2.986 71.701 1.00 69.46 W 3530 OH2 WAT 308 13.414 −6.967 32.790 1.00 65.31 W 3531 OH2 WAT 309 33.466 −3.525 30.583 1.00 62.35 W 3532 OH2 WAT 310 16.536 −26.252 50.513 1.00 59.40 W 3533 OH2 WAT 311 12.868 −17.768 46.259 1.00 64.49 W 3534 OH2 WAT 312 38.794 −23.819 72.570 1.00 80.28 W 3535 OH2 WAT 313 8.998 18.417 30.866 1.00 68.82 W 3536 OH2 WAT 314 34.911 8.822 19.832 1.00 73.20 W 3537 OH2 WAT 315 8.915 −3.801 49.634 1.00 61.40 W 3538 OH2 WAT 316 38.660 11.497 31.752 1.00 68.73 W 3539 OH2 WAT 317 16.707 −21.982 69.442 1.00 60.76 W 3540 OH2 WAT 318 12.028 −10.177 28.742 1.00 70.20 W 3541 OH2 WAT 319 5.774 −5.828 54.505 1.00 65.34 W 3542 OH2 WAT 320 39.266 1.301 38.833 1.00 58.62 W 3543 OH2 WAT 321 18.343 27.444 61.597 1.00 62.10 W 3544 OH2 WAT 322 20.903 −21.561 66.845 1.00 63.88 W 3545 OH2 WAT 323 34.493 10.466 21.876 1.00 70.53 W 3546 OH2 WAT 324 15.691 −1.283 30.803 1.00 63.76 W 3547 OH2 WAT 325 26.634 8.299 68.122 1.00 62.31 W 3548 OH2 WAT 326 25.919 −3.163 33.600 1.00 59.63 W 3549 OH2 WAT 327 38.618 −14.348 44.238 1.00 73.50 W 3550 OH2 WAT 328 11.465 2.147 50.403 1.00 60.62 W 3551 OH2 WAT 329 28.096 32.068 40.827 1.00 76.59 W 3552 OH2 WAT 330 36.452 12.479 48.769 1.00 62.77 W 3553 OH2 WAT 331 30.966 .750 44.943 1.00 51.62 W 3554 OH2 WAT 332 21.804 7.976 19.945 1.00 67.83 W 3555 OH2 WAT 333 15.722 32.585 24.096 1.00 68.69 W 3556 OH2 WAT 334 21.998 −17.667 32.451 1.00 71.85 W 3557 OH2 WAT 335 16.570 28.743 18.262 1.00 55.46 W 3558 OH2 WAT 336 15.355 29.463 26.907 1.00 56.68 W 3559 OH2 WAT 337 8.856 −4.842 42.494 1.00 57.55 W 3560 OH2 WAT 338 15.673 11.399 16.679 1.00 70.26 W 3561 OH2 WAT 339 30.499 −19.038 31.070 1.00 70.97 W 3562 OH2 WAT 340 27.359 6.348 14.986 1.00 76.17 W 3563 OH2 WAT 341 30.716 22.063 48.368 1.00 68.15 W 3564 OH2 WAT 342 17.680 32.354 47.113 1.00 74.87 W 3565 OH2 WAT 343 35.483 −23.224 64.528 1.00 67.43 W 3566 OH2 WAT 344 11.697 33.674 34.831 1.00 62.19 W 3567 OH2 WAT 345 35.198 −13.847 37.632 1.00 62.48 W 3568 OH2 WAT 346 10.971 −16.646 58.283 1.00 62.08 W 3569 OH2 WAT 347 35.865 −19.311 48.930 1.00 81.00 W 3570 OH2 WAT 348 28.051 −8.076 32.451 1.00 59.05 W 3571 OH2 WAT 349 −.526 20.824 45.987 1.00 73.19 W 3572 OH2 WAT 350 8.474 8.048 19.652 1.00 64.06 W 3573 OH2 WAT 351 39.937 7.489 45.216 1.00 63.27 W 3574 OH2 WAT 352 22.499 33.878 48.685 1.00 83.81 W 3575 OH2 WAT 353 36.190 −18.010 40.240 1.00 67.93 W 3576 OH2 WAT 354 6.583 19.327 31.179 1.00 75.92 W 3577 OH2 WAT 355 26.767 −23.288 43.403 1.00 67.04 W 3578 OH2 WAT 356 34.980 17.377 43.331 1.00 79.59 W 3579 OH2 WAT 357 29.121 3.825 23.022 1.00 64.97 W 3580 OH2 WAT 358 25.233 31.185 47.412 1.00 73.20 W 3581 OH2 WAT 359 21.888 −20.887 35.998 1.00 69.44 W 3582 OH2 WAT 360 41.720 −3.130 67.884 1.00 75.17 W 3583 OH2 WAT 361 22.416 −22.509 42.179 1.00 70.22 W 3584 OH2 WAT 362 15.091 −13.586 69.147 1.00 63.87 W 3585 OH2 WAT 363 14.937 −22.535 38.211 1.00 68.35 W 3586 OH2 WAT 364 42.980 −9.148 57.776 1.00 76.86 W 3587 OH2 WAT 365 21.401 −27.138 53.645 1.00 69.72 W 3588 OH2 WAT 366 10.544 −14.952 49.512 1.00 70.21 W 3589 OH2 WAT 367 12.408 3.801 61.011 1.00 62.31 W 3590 OH2 WAT 368 17.248 3.048 21.572 1.00 73.21 W 3591 OH2 WAT 369 20.917 10.215 62.345 1.00 65.29 W 3592 OH2 WAT 370 5.740 −1.049 37.946 1.00 76.08 W 3593 OH2 WAT 371 29.669 20.684 19.121 1.00 55.22 W 3594 OH2 WAT 372 40.853 −3.980 50.418 1.00 66.08 W 3595 OH2 WAT 373 16.357 33.776 29.111 1.00 72.95 W 3596 OH2 WAT 374 36.736 −21.310 42.144 1.00 75.04 W 3597 OH2 WAT 375 36.717 −1.394 68.084 1.00 57.39 W 3598 OH2 WAT 376 12.701 25.019 63.285 1.00 69.21 W 3599 OH2 WAT 377 9.461 .079 38.572 1.00 77.06 W 3600 OH2 WAT 378 29.550 −18.594 40.998 1.00 56.42 W 3601 OH2 WAT 379 37.002 33.477 33.637 1.00 69.48 W 3602 OH2 WAT 380 17.262 −22.386 60.944 1.00 73.34 W 3603 OH2 WAT 381 7.106 −5.199 74.381 1.00 73.24 W 3604 OH2 WAT 382 6.647 15.158 23.410 1.00 70.12 W 3605 C1 NAR 501 26.934 18.860 35.807 1.00 61.49 C 3606 C2 NAR 501 25.603 18.872 36.077 1.00 61.57 C 3607 C3 NAR 501 24.640 19.829 35.382 1.00 61.65 C 3608 C4 NAR 501 25.166 20.681 34.454 1.00 61.63 C 3609 C5 NAR 501 26.686 20.701 34.114 1.00 61.58 C 3610 C6 NAR 501 27.487 19.826 34.771 1.00 61.51 C 3611 C7 NAR 501 24.264 21.692 33.683 1.00 61.64 C 3612 C8 NAR 501 25.045 22.668 32.819 1.00 61.66 C 3613 C9 NAR 501 26.289 22.040 32.224 1.00 61.75 C 3614 O1 NAR 501 27.185 21.564 33.186 1.00 61.71 C 3615 C10 NAR 501 26.971 23.031 31.318 1.00 61.82 C 3616 C11 NAR 501 27.122 24.342 31.687 1.00 61.81 C 3617 C12 NAR 501 27.816 25.322 30.758 1.00 61.88 C 3618 C13 NAR 501 28.301 24.922 29.555 1.00 61.89 C 3619 C14 NAR 501 28.134 23.466 29.145 1.00 61.92 C 3620 C15 NAR 501 27.516 22.579 29.964 1.00 61.83 C 3621 O2 NAR 501 23.058 21.704 33.750 1.00 61.67 C 3622 O3 NAR 501 23.309 19.817 35.673 1.00 61.77 C 3623 O4 NAR 501 27.748 17.997 36.444 1.00 61.35 C 3624 O5 NAR 501 28.915 25.800 28.743 1.00 62.05 C 3625 C1 NAR 502 33.796 −8.354 57.778 1.00 89.25 D 3626 C2 NAR 502 32.541 −8.861 57.702 1.00 89.23 D 3627 C3 NAR 502 32.089 −10.035 58.559 1.00 89.22 D 3628 C4 NAR 502 33.006 −10.560 59.428 1.00 89.20 D 3629 C5 NAR 502 34.440 −10.025 59.563 1.00 89.20 D 3630 C6 NAR 502 34.797 −8.975 58.766 1.00 89.23 D 3631 C7 NAR 502 32.694 −11.745 60.364 1.00 89.18 D 3632 C8 NAR 502 33.367 −11.607 61.741 1.00 89.17 D 3633 C9 NAR 502 34.687 −10.819 61.746 1.00 89.16 D 3634 O1 NAR 502 35.279 −10.623 60.468 1.00 89.18 D 3635 C10 NAR 502 35.618 −11.507 62.726 1.00 89.13 D 3636 C11 NAR 502 36.217 −12.703 62.422 1.00 89.10 D 3637 C12 NAR 502 37.149 −13.377 63.431 1.00 89.06 D 3638 C13 NAR 502 37.396 −12.810 64.648 1.00 89.05 D 3639 C14 NAR 502 36.727 −11.482 64.979 1.00 89.06 D 3640 C15 NAR 502 35.896 −10.874 64.092 1.00 89.12 D 3641 O2 NAR 502 31.989 −12.680 60.059 1.00 89.20 D 3642 O3 NAR 502 30.824 −10.521 58.461 1.00 89.25 D 3643 O4 NAR 502 34.142 −7.311 56.993 1.00 89.32 D 3644 O5 NAR 502 38.221 −13.408 65.539 1.00 89.04 D 3645 S1 SUL 601 29.329 15.428 57.928 1.00 72.96 E 3646 O1 SUL 601 28.642 16.617 57.309 1.00 73.02 E 3647 O2 SUL 601 28.473 14.847 58.999 1.00 73.02 E 3648 O3 SUL 601 30.643 15.853 58.538 1.00 73.11 E 3649 O4 SUL 601 29.610 14.436 56.850 1.00 73.00 E 3650 S1 SUL 602 35.827 −2.534 36.136 1.00 74.42 F 3651 O1 SUL 602 35.316 −1.739 37.305 1.00 74.49 F 3652 O2 SUL 602 35.956 −3.971 36.514 1.00 74.45 F 3653 O3 SUL 602 37.188 −2.019 35.723 1.00 74.53 F 3654 O4 SUL 602 34.874 −2.354 34.996 1.00 74.40 F 3655 S1 SUL 603 23.022 36.796 31.551 1.00 84.30 G 3656 O1 SUL 603 24.269 37.382 32.155 1.00 84.26 G 3657 O2 SUL 603 22.893 35.383 31.991 1.00 84.22 G 3658 O3 SUL 603 23.099 36.815 30.053 1.00 84.26 G 3659 O4 SUL 603 21.855 37.634 31.971 1.00 84.28 G 3660 S1 SUL 604 28.867 23.364 40.821 1.00 71.85 H 3661 O1 SUL 604 28.898 22.850 39.401 1.00 71.90 H 3662 O2 SUL 604 27.477 23.295 41.360 1.00 71.86 H 3663 O3 SUL 604 29.322 24.801 40.860 1.00 71.98 H 3664 O4 SUL 604 29.814 22.540 41.641 1.00 71.87 H 3665 S1 SUL 605 37.472 −10.233 53.632 1.00 90.38 I 3666 O1 SUL 605 38.162 −10.843 54.827 1.00 90.36 I 3667 O2 SUL 605 36.461 −11.177 53.085 1.00 90.34 I 3668 O3 SUL 605 38.480 −9.940 52.560 1.00 90.32 I 3669 O4 SUL 605 36.839 −8.942 54.058 1.00 90.34 I

“Structure coordinates” refers to Cartesian coordinates (x, y, and z positions) derived from mathematical equations involving Fourier synthesis as determined from patterns obtained via diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) of an isomerase polypeptide in crystal form. Diffraction data are used to calculate electron density maps of repeating protein units in the crystal (unit cell). Electron density maps are used to establish the positions of individual atoms within a crystal's unit cell. The term “crystal structure coordinates” refers to mathematical coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) of an isomerase polypeptide (e.g., a chalcone isomerase protein molecule) in crystal form. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are used to establish the positions of the individual atoms within the unit cell of the crystal. The crystal structure coordinates of an isomerase can be obtained from a chalcone isomerase protein crystal having space group P6₅22 (a=90.37 Å, c=352.86 Å with two molecules per asymmetric unit and a solvent content of 72%). The coordinates of the isomerase polypeptide can also be obtained by means of computational analysis.

The term “selenomethionine substitution” refers to the method of producing a chemically modified form of the crystal of an isomerase (e.g., a chalcone isomerase). The isomerase protein is expressed by bacteria in media that is depleted in methionine and supplement with selenomethionine. Selenium is thereby incorporated into the crystal in place of methionine sulfurs. The location(s) of selenium are determined by X-ray diffraction analysis of the crystal. This information is used to generate the phase information used to construct a three-dimensional structure of the protein.

“Heavy atom derivatization” refers to a method of producing a chemically modified form of an isomerase crystal. In practice, a crystal is soaked in a solution containing heavy atom salts or organometallic compounds, e.g., lead chloride, gold thiomalate, thimerosal, uranyl acetate, and the like, which can diffuse through the crystal and bind to the protein's surface. Locations of the bound heavy atoms can be determined by X-ray diffraction analysis of the soaked crystal. This information is then used to construct phase information which can then be used to construct three-dimensional structures of the enzyme as described in Blundel, T. L., and Johnson, N. L., Protein Crystallography, Academic Press (1976), which is incorporated herein by reference.

“Unit cell” refers to a basic parallelepiped shaped block. Regular assembly of such blocks may construct the entire volume of a crystal. Each unit cell comprises a complete representation of the unit pattern, the repetition of which builds up the crystal.

“Space Group” refers to the arrangement of symmetry elements within a crystal.

“Molecular replacement” refers to generating a preliminary model of an isomerase whose structural coordinates are unknown, by orienting and positioning a molecule whose structural coordinates are known within the unit cell of the unknown crystal so as best to account for the observed diffraction pattern of the unknown crystal. Phases can then be calculated from this model and combined with the observed amplitudes to give an approximate Fourier synthesis of the structure whose coordinates are unknown. This in turn can be subject to any of the several forms of refinement to provide a final, accurate structure of the unknown crystal (Lattman, E., 1985, in Methods in Enzymology, 11 5.55-77; Rossmann, M G., ed., “The Molecular Replacement Method” 1972, Int, Sci. Rev. Ser., No. 13, Gordon & Breach, New York). Using structure coordinates of the isomerase provided herein, molecular replacement may be used to determine the structural coordinates of a crystalline mutant, homologue, or a different crystal form of an isomerase.

“Substrate” refers to chalcone and 6′ deoxychalcone that are acted on by the chalcone isomerases and mutants thereof disclosed herein, and the like.

“Altered substrate specificity” includes a change in the ability of a mutant isomerase to produce a flavonoid product as compared to a non-mutated isomerase. Altered substrate specificity may include the ability of an isomerase to exhibit different enzymatic parameters relative to a non-mutated isomerase (K_(m), V_(max), etc.), use different substrates, and/or produce products that are different from those of known non-native isomerases.

A polypeptide is a chain of amino acids, regardless of length or post-translational modification (e.g., glycosylation or phosphorylation). A polypeptide or protein refers to a polymer in which the monomers are amino acid residues, which are joined together through amide bonds. When the amino acids are alpha-amino acids, either the L-optical isomer or the D-optical isomer can be used, the L-isomers being typical. An isomerase polypeptide of the invention is intended to encompass an amino acid sequence as set forth in SEQ ID NO:1 (see, Table 2) or SEQ ID NO:1 having one or more mutations, mutants, variants and conservative substitutions thereof comprising L- or D-amino acids and include modified sequences such as glycoproteins.

TABLE 2 (SEQ ID NO: 1) maasitaitv enleypavvt spvtgksyfl ggagerglti egnfikftai gvylediava slaakwkgks seelletldf yrdiisgpfe klirgskire lsgpeysrkv mencvahlks vgtygdaeae amqkfaeafk pvnfppgasv fyrqspdgil glsfspdtsi pekeaalien kavssavlet migehavspd lkrclaarlp allnegafki gn

Accordingly, the polypeptides of the invention are intended to cover naturally occurring proteins, as well as those which are recombinantly or synthetically synthesized. Polypeptide or protein fragments are also encompassed by the invention. Fragments can have the same or substantially the same amino acid sequence as the naturally occurring protein. A polypeptide or peptide having substantially the same sequence means that an amino add sequence is largely, but not entirely, the same, but retains a functional activity of the sequence to which it is related. In general polypeptides of the invention include peptides, or full-length protein, that contains substitutions, deletions, or insertions into the protein backbone, that would still have an approximately 70%-90% homology to the original protein over the corresponding portion. A yet greater degree of departure from homology is allowed if like-amino acids, i.e. conservative amino acid substitutions, do not count as a change in the sequence.

A polypeptide may be substantially related but for a conservative variation, such polypeptides being encompassed by the invention. A conservative variation denotes the replacement of an amino acid residue by another, biologically similar residue. Examples of conservative variations include the substitution of one hydrophobic residue such as isoleucine, valine, leucine or methionine for another, or the substitution of one polar residue for another, such as the substitution of arginine for lysine, glutamic for aspartic acids, or glutamine for asparagine, and the like. Other illustrative examples of conservative substitutions include the changes of: alanine to serine; arginine to lysine; asparagine to glutamine or histidine; aspartate to glutamate; cysteine to serine; glutamine to asparagine; glutamate to aspartate; glycine to proline; histidine to asparagine or glutamine; isoleucine to leucine or valine; leucine to valine or isoleucine; lysine to arginine, glutamine, or glutamate; methionine to leucine or isoleucine; phenylalanine to tyrosine, leucine or methionine; serine to threonine; threonine to serine; tryptophan to tyrosine; tyrosine to tryptophan or phenylalanine; valine to isoleucine or leucine, and the like. The term “conservative variation” also includes the use of a substituted amino acid in place of an unsubstituted parent amino acid provided that antibodies raised to the substituted polypeptide also immunoreact with the unsubstituted polypeptide.

Modifications and substitutions are not limited to replacement of amino acids. For a variety of purposes, such as increased stability, solubility, or configuration concerns, one skilled in the art will recognize the need to introduce other modifications, for example, deletion(s), replacement(s) or addition(s). Examples of such other modifications include incorporation of rare amino adds, dextra-amino acids, glycosylation sites, cytosine for specific disulfide bridge formation. The modified peptides can be chemically synthesized, or the isolated gene can be subjected to site-directed mutagenesis, or a synthetic gene can be synthesized and expressed in bacteria, yeast, baculovirus, tissue culture and so on.

Polypeptides of the invention include isomerase polypeptides (e.g., chalcone isomerase) from any number of plants, prokaryotes, eukaryotes, including, for example, invertebrates, mammals and humans and include sequences as set forth in SEQ ID NO:1 through SEQ ID NO:8, as well as sequences that have at least 70% homology to the sequence of SEQ ID NO:1 through SEQ ID NO:8, fragments, variants, or conservative substitutions of any of the foregoing sequences.

The term “variant” refers to polypeptides which are modified at one or more amino acid residues yet still retain the biological activity of an isomerase polypeptide. Variants can be produced by any number of means known in the art, including methods such as, for example, error-prone PCR, shuffling, oligonucleotide-directed mutagenesis, assembly PCR, sexual PCR mutagenesis, and the like, as well as any combination thereof.

By “substantially identical” is meant a polypeptide or nucleic acid exhibiting at least 50%, preferably 85%, more preferably 90%, and most preferably 95% homology to a reference amino acid or nucleic acid sequence.

Homology or identity is often measured using sequence analysis software (e.g., Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705). Such software matches similar sequences by assigning degrees of homology to various deletions, substitutions and other modifications. The terms “homology” and “identity” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino add residues or nucleotides that are the same when compared and aligned for maximum correspondence over a comparison window or designated region as measured using any number of sequence comparison algorithms or by manual alignment and visual inspection.

For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters.

A “comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequence for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482, 1981, by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443, 1970, by the search for similarity method of Person & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444, 1988, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection. Other algorithms for determining homology or identity include, for example, in addition to a BLAST program (Basic Local Alignment Search Tool at the National Center for Biological Information), ALIGN, AMAS (Analysis of Multiply Aligned Sequences), AMPS (Protein Multiple Sequence Alignment), ASSET (Aligned Segment Statistical Evaluation Tool), BANDS, BESTSCOR, BIOSCAN (Biological Sequence Comparative Analysis Node), BLIMPS (BLocks IMProved Searcher), FASTA, Intervals & Points, BMB, CLUSTAL V, CLUSTAL W, CONSENSUS, LCONSENSUS, WCONSENSUS, Smith-Waterman algorithm, DARWIN, Las Vegas algorithm, FNAT (Forced Nucleotide Alignment Tool), Framealign, Framesearch, DYNAMIC, FILTER, FSAP (Fristensky Sequence Analysis Package), GAP (Global Alignment Program), GENAL, GIBBS, GenQuest, ISSC (Sensitive Sequence Comparison), LALIGN (Local Sequence Alignment), LCP (Local Content Program), MACAW (Multiple Alignment Construction & Analysis Workbench), MAP (Multiple Alignment Program), MBLKP, MBLKN, PIMA (Pattern-Induced Multi-sequence Alignment), SAGA (Sequence Alignment by Genetic Algorithm) and WHAT-IF. Such alignment programs can also be used to screen genome databases to identify polynucleotide sequences having substantially identical sequences. A number of genome databases are available, for example, a substantial portion of the human genome is available as part of the Human Genome Sequencing Project (J. Roach, available on the World Wide Web at weber.u.Washington.edu/˜roach/human_genome_progress 2.html) (Gibbs, 1995). At least twenty-one other genomes have already been sequenced, including, for example, M. genitalium (Fraser et al., 1995), M. jannaschii (Bult et al., 1996), H. influenzae (Fleischmann et al., 1995), E. coli (Blattner et al., 1997), and yeast (S. cerevisiae) (Mewes et al., 1997), and D. melanogaster (Adams et al., 2000). Significant progress has also been made in sequencing the genomes of model organism, such as mouse, C. elegans, and Arabadopsis sp. Several databases containing genomic information annotated with some functional information are maintained by different organization, and are accessible via the internet, for example, on the World Wide Web at tigr.org/tdb, genetics.wisc.edu, standford.edu/˜ball, hiv-web.lanl.gov, ncbi.nlm.nih.gov, ebi.ac.uk, Pasteur.fr/other/biology, and genome.wi.mit.edu.

One example of a useful algorithm is BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., Nuc. Acids Res. 25:3389-3402, 1977, and Altschul et al., J. Mol. Biol. 215:403-410, 1990, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (available on the World Wide Web at ncbi.nlm.nih.gov). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, an expectation (E) of 10, M=5, N=−4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a wordlength of 3, and expectations (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915, 1989) alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and a comparison of both strands.

The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. Natl. Acad. Sci. USA 90:5873, 1993). One measure of similarity provided by BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a references sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

In one embodiment, protein and nucleic acid sequence homologies are evaluated using the Basic Local Alignment Search Tool (“BLAST”) In particular, five specific BLAST programs are used to perform the following task:

-   -   (1) BLASTP and BLAST3 compare an amino acid query sequence         against a protein sequence database;     -   (2) BLASTN compares a nucleotide query sequence against a         nucleotide sequence database;     -   (3) BLASTX compares the six-frame conceptual translation         products of a query nucleotide sequence (both strands) against a         protein sequence database;     -   (4) TBLASTN compares a query protein sequence against a         nucleotide sequence database translated in all six reading         frames (both strands); and     -   (5) TBLASTX compares the six-frame translations of a nucleotide         query sequence against the six-frame translations of a         nucleotide sequence database.

The BLAST programs identify homologous sequences by identifying similar segments, which are referred to herein as “high-scoring segment pairs,” between a query amino or nucleic acid sequence and a test sequence which is preferably obtained from a protein or nucleic acid sequence database. High-scoring segment pairs are preferably identified (i.e., aligned) by means of a scoring matrix, many of which are known in the art. Preferably, the scoring matrix used is the BLOSUM62 matrix (Gonnet et al., Science 256:1443-1445, 1992; Henikoff and Henikoff, Proteins 17:49-61, 1993). Less preferably, the PAM or PAM250 matrices may also be used (see, e.g., Schwartz and Dayhoff, eds., 1978, Matrices for Detecting Distance Relationships: Atlas of Protein Sequence and Structure, Washington: National Biomedical Research Foundation). BLAST programs are accessible through the U.S. National Library of Medicine, e.g., on the World Wide Web at ncbi.nlm.nih.gov.

The parameters used with the above algorithms may be adapted depending on the sequence length and degree of homology studied. In some embodiments, the parameters may be the default parameters used by the algorithms in the absence of instructions from the user.

One aspect of the invention resides in obtaining crystals of the isomerase polypeptide (e.g., chalcone isomerase) of sufficient quality to determine the three dimensional (tertiary) structure of the protein by X-ray diffraction methods. The knowledge obtained concerning the three-dimensional structure of chalcone isomerase can be used in the determination of the three dimensional structure of other isomerase polypeptides in the polyketide synthesis or flavonoid pathway. The structural coordinates of chalcone isomerase can be used to develop new isomerase enzymes or isomerase binding agents (e.g., inhibitors or substrates) using various computer models. Based on the structural coordinates of the chalcone isomerase polypeptide (e.g., the three dimensional protein structure), as described herein, novel isomerases can be engineered. In addition, small molecules which mimic or are capable of interacting with a functional domain of an isomerase polypeptide, can be designed and synthesized to modulate chalcone isomerase and other isomerase biological functions as well as the biological functions of other flavanone-related isomerases. Accordingly, in one embodiment, the invention provides a method of “rational” enzyme or drug design.

Another approach to “rational” enzyme or drug design is based on a lead compound that is discovered using high throughput screens; the lead compound is further modified based on a crystal structure of the binding regions of the molecule in question. Accordingly, another aspect of the invention is to provide related protein sequences or material which is a starting material in the rational design of new isomerases or drugs which lead to the synthesis of new flavonoids or modify the flavonoid pathway.

The present invention relates to crystallized isomerases and mutants thereof from which the position of specific α-carbon atoms and R-groups associated therewith comprising the active site can be determined in three-dimensional space. The invention also relates to structural coordinates of said chalcone isomerases, use of said structural coordinates to develop structural information related to isomerase homologues, mutants, and the like, and to crystal forms of such isomerases. Furthermore, the invention, as disclosed herein, provides a method whereby the α-carbon structural coordinates specifically determined for atoms comprising the active site of the isomerase can be used to develop isomerases wherein R-groups associated with active site α-carbon atoms are different from the R-groups found in native CHI, e.g., are mutant isomerases. In addition, the present invention provides for production of mutant chalcone isomerases based on the structural information provided herein and for use of the mutant isomerases to make a variety of flavonoid or polyketide compounds using a variety of substrates.

The present invention further provides, for the first time, crystal isomerases, as exemplified by chalcone isomerase (CHI; PDB Accession No. 1EYP, SEQ ID NOs:9-11) see Table 1 for coordinates of native CHI (SEQ ID NO:1).

Also provided are coordinates for crystals which are grown in the presence and absence of product and product analogues, thus allowing definition of the structural or atomic coordinates associated therewith. The structural coordinates allow determination of the α-carbon atoms comprising the active site, R-groups associated therewith, and the interaction of said α-carbons and said R-groups with each other. For example, CHI (SEQ ID NO:9) was co-crystallized with naringenin as a complex. Other crystallized complexes include CHI (SEQ ID NO:9) complexed with 5-deoxyflavanone and CHI (SEQ ID NO:9) complexed with 5,4′-dideoxyflavanone (PDB accession numbers 1FM7 and 1FM8, respectively, which were deposited on Aug. 16, 2000) and CHI (SEQ ID NO:9) complexed with 4′-dihydroxyflavanone (Accession No. 1JEP, Protein Data Bank). The crystals of CHI•naringenin belong to space group P6₅22 having unit cell dimensions of a=89.47 Å; c=351.19 Å, α=β=90°, γ=120° with a single monomer per asymmetric unit.

Crystal structures are preferably obtained at a resolution of about 1.56 angstroms to about 3 angstroms for an isomerase in the presence and in the absence of bound product or product analog. Coordinates for an isomerase in the absence of a substrate bound in the active site have been deposited at the Brookhaven National Laboratory Protein Data Bank, accession number 1EYP (SEQ ID NOs:9-11). Those skilled in the art understand that a set of structure coordinates determined by X-ray crystallography is not without standard error. Therefore, for the purpose of this invention, any set of structure coordinates wherein the active site α-carbons of an isomerase, isomerase homologue, or mutants thereof, have a root mean square deviation less than ±2.3 angstroms when superimposed using the structural coordinates listed in Table 1 and PDB Accession No. 1EYP, shall be considered identical.

CHI is a functional monomer of approximately 220 residues and has been isolated from a variety of higher plants. The overall structure of CHI resembles an upside-down bouquet that adopts an open-faced β-sandwich fold (FIGS. 1B and 1C). A large β-sheet β3a-β3f) and a layer of α-helices (α1-α7) comprise the core structure with three short β-strands (β1a, β1b, β2) on the opposite side of the large β-sheet. A search of the Protein Data Bank using DALI revealed no other structurally homologous folds. In addition, a PSI-BLAST search of sequence databases showed that CHI-like sequences are typically found in plants and these sequences display no detectable homology with other proteins. Amino acid sequence comparison of CHIs (SEQ ID NOs:1-8) from a variety of advanced land plants reveals high homology (49% to 82% amino acid sequence identity) with regions of conservation spread uniformly throughout the primary structure (FIG. 1D). Interestingly, there is conservation of residues spanning β3a, β3b, α4, and α6 in the three-dimensional structure among CHIs from different species. Notably, these structural elements form the active site on the protein surface.

The active site α-carbons of chalcone isomerase generally are not all contiguous, i.e., are not adjacent to one another in the primary amino acid sequence of the isomerase due to intervening amino acid residues between various active site α-carbons. Nevertheless, it should be appreciated that certain active site α-carbons can be adjacent to one another in some instances.

An appropriate combination of R-groups, linked to active site α-carbons, can facilitate the formation of one or more desired reaction products. The combination of R-groups selected for use in an isomerase can be any combination other than the ordered arrangements of R-groups found in known native isomerases. Typically, R-groups found on active site α-carbons are those found in naturally occurring amino acids. In some embodiments, however, R-groups other than those found in naturally occurring amino acids can be used.

The present invention permits the use of molecular design techniques to design, select, and synthesize genes encoding mutant isomerases and chalcone isomerases that produce different and/or novel flavonoid compounds using various substrates. Mutant proteins of the present invention and nucleic acids encoding the same can be designed by genetic manipulation based on structural information provided herein for the first time regarding isomerases. For example, one or more R-groups associated with the active site α-carbon atoms of CHI can be changed by altering the nucleotide sequence of the corresponding CHI gene, thus making one or more mutant chalcone isomerases. Such genetic manipulations can be guided by structural information concerning the R-groups found in the active site α-carbons when substrate is bound to the protein upon crystallization.

Mutant proteins of the present invention may be prepared in a number of ways available to the skilled artisan. For example, the gene encoding wild-type CHI may be mutated at those sites identified herein as corresponding to amino acid residues identified in the active site by means currently available to the artisan skilled in molecular biology techniques. Such techniques include oligonucleotide-directed mutagenesis, deletion, chemical mutagenesis, and the like. The protein encoded by the mutant gene is then produced by expressing the gene in, for example, a bacterial or plant expression system.

Alternatively, isomerase mutants may be generated by site specific-replacement of a particular amino acid with an unnaturally occurring amino acid or mimetic. As such, isomerase mutants may be generated through replacement of an amino acid residue or a particular cysteine or methionine residue with selenocysteine or selenomethionine. This may be achieved by growing a host organism capable of expressing either the wild-type or mutant polypeptide on a growth medium depleted of natural cysteine or methionine or both and growing on medium enriched with either selenocysteine, selenomethionine, or both. These and similar techniques are described in Sambrook et al., (Molecular Cloning, A Laboratory Manual, 2^(nd) Ed. (1989) Cold Spring Harbor Laboratory Press).

Another suitable method of creating mutant isomerases of the present invention is based on a procedure described in Noel and Tsal, J. Cell. Biochem., 40:309-320, 1989. In so doing, the nucleic acids encoding the isomerase can be synthetically produced using oligonucleotides having overlapping regions, said oligonucleotides being degenerate at specific bases so that mutations are induced.

According to the present invention, nucleic acid sequences encoding a mutated polyketide isomerase can be produced by the methods described herein, or any alternative methods available to the skilled artisan. In designing the nucleic acid sequence of interest, it may be desirable to reengineer the gene for improved expression in a particular expression system. For example, it has been shown that many bacterially derived genes do not express well in plant systems. In some cases, plant-derived genes do not express well in bacteria. This phenomenon may be due to the non-optimal G+C content and/or A+T content of said gene relative to the expression system being used. For example, the very low G+C content of many bacterial genes results in the generation of sequences mimicking or duplicating plant gene control sequences that are highly A+T rich. The presence of A+T rich sequences within the genes introduced into plants (e.g., TATA box regions normally found in promoters) may result in aberrant transcription of the gene(s). In addition, the presence of other regulatory sequences residing in the transcribed mRNA (e.g. polyadenylation signal sequences (AAUAAA) or sequences complementary to small nuclear RNAs involved in pre-mRNA splicing) may lead to RNA instability. Therefore, one goal in the design of genes is to generate nucleic acid sequences that have a G+C content that affords mRNA stability and translation accuracy for a particular expression system.

Due to the plasticity afforded by the redundancy of the genetic code (i.e., some amino acids are specified by more than one codon), evolution of the genomes of different organisms or classes of organisms has resulted in differential usage of redundant codons. This “codon bias” is reflected in the mean base composition of protein coding regions. For example, organisms with relatively low G+C contents utilize codons having A or T in the third position of redundant codons, whereas those having higher G+C contents utilize codons having G or C in the third position. Therefore, in reengineering genes for expression, one may wish to determine the codon bias of the organism in which the gene is to be expressed. Looking at the usage of the codons as determined for genes of a particular organism deposited in GenBank can provide this information. After determining the bias thereof, the new gene sequence can be analyzed for restriction enzyme sites as well as other sites that could affect transcription such as exon:intron junctions, polyA addition signals, or RNA polymerase termination signals.

Genes encoding isomerases, such as chalcone isomerase, can be placed in an appropriate vector, depending on the artisan's interest, and can be expressed using a suitable expression system. An expression vector, as is well known in the art, typically includes elements that permit replication of said vector within the host cell and may contain one or more phenotypic markers for selection of cells containing the gene. The expression vector will typically contain sequences that control expression such as promoter sequences, ribosome binding sites, and translational initiation and termination sequences. Expression vectors may also contain elements such as subgenomic promoters, a repressor gene or various activator genes. The artisan may also choose to include nucleic acid sequences that result in secretion of the gene product, movement of said product to a particular organelle such as a plant plastid (see U.S. Pat. Nos. 4,762,785; 5,451,513 and 5,545,817, which are incorporated herein by reference) or other sequences that increase the ease of peptide purification, such as an affinity tag.

A wide variety of expression control sequences are useful in expressing native or mutated isomerases when operably linked thereto. Such expression control sequences include, for example, the early and late promoters of SV40 for animal cells, the lac system, the trp system, major operator and promoter systems of phage S, and the control regions of coat proteins, particularly those from RNA viruses in plants. In E. coli, a useful transcriptional control sequence is the T7 RNA polymerase binding promoter, which can be incorporated into a pET vector as described by Studier et al., Methods Enzymology, 185:60-89, 1990, which is incorporated herein by reference.

For expression, a desired gene should be operably linked to the expression control sequence and maintain the appropriate reading frame to permit production of the desired isomerase. Any of a wide variety of well-known expression vectors are of use to the present invention. These include, for example, vectors comprising segments of chromosomal, non-chromosomal and synthetic DNA sequences such as those derived from SV40, bacterial plasmids including those from E. coli such as col E1, pCR1, pBR322 and derivatives thereof, pMB9, wider host range plasmids such as RP4, phage DNA such as phage S, NM989, M13, and other such systems as described by Sambrook et al., (Molecular Cloning, A Laboratory Manual, 2^(nd) Ed. (1989) Cold Spring Harbor Laboratory Press), which is incorporated herein by reference.

A wide variety of host cells are available for expressing isomerase mutants of the present invention. Such host cells include, for example, bacteria such as E. coli, Bacillus and Streptomyces, fungi, yeast, animal cells, plant cells, insect cells, and the like. Preferred embodiments of the present invention include chalcone isomerase mutants that are expressed in E. coli or in plant cells. Said plant cells can either be in suspension culture or a transgenic plant.

In order to produce transgenic plants, vectors containing the nucleic acid construct encoding isomerases and mutants thereof are inserted into the plant genome. Preferably, these recombinant vectors are capable of stable integration into the plant genome. One variable in making a transgenic plant is the choice of a selectable marker. A selectable marker is used to identify transformed cells against a high background of untransformed cells. The preference for a particular marker is at the discretion of the artisan, but any of the selectable markers may be used along with any other gene not listed herein that could function as a selectable marker. Such selectable markers include aminoglycoside phosphotransferase gene of transposon Tn5 (Aph 11) (which encodes resistance to the antibiotics kanamycin), neomycin, G418, as well as those genes which code for resistance or tolerance to glyphosate, hygromycin, methotrexate, phosphinothricin, imidazolinones, sulfonylureas, triazolopyrimidine herbicides, such as chlorosulfuron, bromoxynil, dalapon, and the like. In addition to a selectable marker, it may be desirable to use a reporter gene. In some instances a reporter gene may be used with a selectable marker. Reporter genes allow the detection of transformed cells and may be used at the discretion of the artisan. A list of these reporter genes is provided in K. Wolsing et al., Ann. Rev. Genetics, 22:421, 1988.

The genes are expressed either by promoters expressing in all tissues at all times (constitutive promoters), by promoters expressing in specific tissues (tissue-specific promoters), promoters expressing at specific stages of development (developmental promoters), and/or promoters expressing in response to a stimulus or stimuli (inducible promoters). The choice of these is at the discretion of the artisan.

Several techniques exist for introducing foreign genes into plant cells, and for obtaining plants that stably maintain and express the introduced gene. Such techniques include acceleration of genetic material coated on a substrate directly into cells (U.S. Pat. No. 4,945,050 to Cornell): Plant cells may also be transformed using Agrobacterium technology (see, for example, U.S. Pat. No. 5,177,010 to University of Toledo, U.S. Pat. No. 5,104,310 to Texas A&M, U.S. Pat. Nos. 5,149,645, 5,469,976, 5,464,763, 4,940,838, and 4,693,976 to Schilperoot, European Patent Applications 116718, 290799, 320500 to Max Planck, European Patent Applications 604662, 627752 and U.S. Pat. No. 5,591,616 to Japan Tobacco, European Patent Applications 0267159, 0292435 and U.S. Pat. No. 5,231,011 to Ciba-Geigy, U.S. Pat. Nos. 5,463,174 and 4,762,785 to Calgene, and U.S. Pat. Nos. 5,004,863 and 5,159,135 to Agracetus). Other transformation technologies include whiskers technology (see U.S. Pat. Nos. 5,302,523 and 5,464,765 to Zeneca). Electroporation technology has also been used to transform plants (see WO 87106614 to Boyce Thompson Institute, U.S. Pat. Nos. 5,472,869 and 5,384,253 to Dakalb, and WO 92/09696 and WO 93/21335 to Plant Genetic Systems, all which are incorporated by reference). Viral vector expression systems can also be used such as those described in U.S. Pat. Nos. 5,316,931, 5,589,367, 5,811,653, and 5,866,785 to BioSource, which are incorporated herein by reference.

In addition to numerous technologies for transforming plants, the type of tissue that is contacted with the genes of interest may vary as well. Suitable tissue includes, for example, embryonic tissue, callus tissue, hypocotyl, meristem, and the like. Almost all plant tissues may be transformed during de-differentiation using the appropriate techniques described herein.

Regardless of the transformation system used, a gene encoding a mutant isomerase is preferably incorporated into a gene transfer vector adapted to express said gene in a plant cell by including in the vector an expression control sequence (e.g., a plant promoter regulatory element). In addition to plant promoter regulatory elements, promoter regulatory elements from a variety of sources can be used efficiently in plant cells to express foreign genes. For example, promoter regulatory elements of bacterial origin, such as the octopine synthase promoter, the nopaline synthase promoter, the mannopine synthase promoter, and the like, may be used. Promoters of viral origin, such as the cauliflower mosaic virus (35S and 198) are also desirable. Plant promoter regulatory elements also include ribulose-1,6-bisphosphate carboxylase small subunit promoter, beta-conglycinin promoter, phaseolin promoter, ADH promoter, heat-shock promoters, tissue specific promoters, and the like. Numerous promoters are available to skilled artisans for use at their discretion.

It should be understood that not all expression vectors and expression systems function in the same way to express the mutated gene sequences of the present invention. Neither do all host cells function equally well with the same expression system. However, one skilled in the art may make a selection among these vectors, expression control sequences, and host without undue experimentation and without departing from the scope of this invention.

Once an isomerase of the present invention is expressed, the protein obtained therefrom can be purified so that structural analysis, modeling, and/or biochemical analysis can be performed, as exemplified herein. The nature of the protein obtained can be dependent on the expression system used. For example, genes, when expressed in mammalian or other eukaryotic cells, may contain latent signal sequences that may result in glycosylation, phosphorylation, or other post-translational modifications, which may or may not alter function. Therefore, a preferred embodiment of the present invention is the expression of mutant isomerase genes in E. coli cells. Once the proteins are expressed, they can be easily purified using techniques common to the person having ordinary skill in the art of protein biochemistry, such as, for example, techniques described in Colligan at al., (1997) Current Protocols in Protein Science, Chanda, V. B., Ed., John Wiley & Sons, Inc., which is incorporated herein by reference. Such techniques often include the use of cation-exchange or anion-exchange chromatography, gel filtration-size exclusion chromatography, and the like. Another technique that may be commonly used is affinity chromatography. Affinity chromatography can include the use of antibodies, substrate analogs, or histidine residues (His-tag technology).

Once purified, mutants of the present invention may be characterized by any of several different properties. For example, such mutants may have altered active site surface charges of one or more charge units. In addition, the mutants may have altered substrate specificity or product capability relative to a non-mutated isomerase (e.g., a chalcone isomerase).

The present invention allows for the characterization of isomerase mutants by crystallization followed by X-ray diffraction. Polypeptide crystallization occurs in solutions where the polypeptide concentration exceeds it solubility maximum (i.e., the polypeptide solution is supersaturated). Such solutions may be restored to equilibrium by reducing the polypeptide concentration, preferably through precipitation of the polypeptide crystals. Often polypeptides may be induced to crystallize from supersaturated solutions by adding agents that alter the polypeptide surface charges or perturb the interaction between the polypeptide and bulk water to promote associations that lead to crystallization.

Compounds known as “precipitants” are often used to decrease the solubility of the polypeptide in a concentrated solution by forming an energetically unfavorable precipitating layer around the polypeptide molecules (Weber, Advances in Protein Chemistry, 41:1-36, 1991). In addition to precipitants, other materials are sometimes added to the polypeptide crystallization solution. These include buffers to adjust the pH of the solution and salts to reduce the solubility of the polypeptide. Various precipitants are known in the art and include the following: ethanol, 3-ethyl-2,4-pentanediol, many of the polyglycols (such as polyethylene glycol), and the like.

Commonly used polypeptide crystallization methods include the following techniques: batch, hanging drop, seed initiation, dialysis, and the like. In each of these methods, it is important to promote continued crystallization after nucleation by maintaining a supersaturated solution. In the batch method, polypeptide is mixed with precipitants to achieve supersaturation, the vessel is sealed, and set aside until crystals appear. In the dialysis method, polypeptide is retained in a sealed dialysis membrane that is placed into a solution containing precipitant Equilibration across the membrane increases the polypeptide and precipitant concentrations thereby causing the polypeptide to reach supersaturation levels.

In the preferred hanging drop technique (McPherson, J. Biot Chem, 6300-6306, 1976), an initial polypeptide mixture is created by adding a precipitant to a concentrated polypeptide solution. The concentrations of the polypeptide and precipitants are such that in this initial form, the polypeptide does not crystallize. A small drop of this mixture is placed on a glass slide that is inverted and suspended over a reservoir of a second solution. The system is then sealed. Typically, the second solution contains a higher concentration of precipitant or other dehydrating agent. The difference in the precipitant concentrations causes the protein solution to have a higher vapor pressure than the solution. Since the system containing the two solutions is sealed, an equilibrium is established, and water from the polypeptide mixture transfers to the second solution. This equilibrium increases the polypeptide and precipitant concentration in the polypeptide solution. At the critical concentration of polypeptide and precipitant, a crystal of the polypeptide will form.

Another method of crystallization involves introducing a nucleation site into a concentrated polypeptide solution. Generally, a concentrated polypeptide solution is prepared and a seed crystal of the polypeptide is introduced into this solution. If the concentration of the polypeptide and any precipitants are correct, the seed crystal will provide a nucleation site around which a larger crystal forms. In typical embodiments, the crystals of the present invention are formed in hanging drops with 15% PEG 8000; 200 mM magnesium acetate or magnesium chloride, 100 mM 3-(N-morpholino)-2-hydroxypropanesulfonic acid (pH 7.0), and 1 mM dithiothreitol as precipitant.

Some proteins may be recalcitrant to crystallization. However, several techniques are available to the skilled artisan. Quite often the removal of polypeptide segments at the amino or carboxy terminal end of the protein is necessary to produce crystalline protein samples. Said procedures involve either treatment of the protein with one of several proteases including trypsin, chymotrypsin, substilisin, and the like. This treatment often results in the removal of flexible polypeptide segments that are likely to negatively affect crystallization. Alternatively, the removal of coding sequences from the protein's gene facilitates the recombinant expression of shortened proteins that can be screened for crystallization.

The crystals so produced have a wide range of uses. For example, high quality crystals are suitable for X-ray or neutron diffraction analysis to determine the three-dimensional structure of mutant and native isomerases and to design additional mutants thereof. In addition, crystallization can serve as a further purification method. In some instances, a polypeptide or protein will crystallize from a heterogeneous mixture into crystals. Isolation of such crystals by filtration, centrifugation, etc., followed by redissolving the polypeptide affords a purified solution suitable for use in growing the high-quality crystals needed for diffraction studies. The high-quality crystals may also be dissolved in water and then formulated to provide an aqueous solution having other uses as desired.

Because isomerases may crystallize in more than one crystal form, the structural coordinates of α-carbons of an active site determined from an isomerase or portions thereof, as provided by this invention, are particularly useful to solve the structure of other crystal forms of isomerases. The structural coordinates, as provided herein, may also be used to solve the structure of isomerases having α-carbons positioned within the active sites in a manner similar to the wild-type isomerase, yet having R-groups that may or may not be identical to the wild-type isomerase.

Furthermore, the structural coordinates disclosed herein may be used to determine the structure of the crystalline form of other proteins with significant amino acid or structural homology to any functional domain of an isomerase. One method that may be employed for such purpose is molecular replacement. In this method, the unknown crystal structure, whether it is another crystal form of an isomerase, an isomerase having a mutated active site, or the crystal of some other protein with significant sequence and/or structural homology to an isomerase may be determined using the coordinates given in Table 1. This method provides sufficient structural form for the unknown crystal more efficiently than attempting to determine such information ab initio. In addition, this method can be used to determine whether or not a given isomerase in question falls within the scope of this invention.

As further disclosed herein, isomerases and mutants thereof may be crystallized in the presence or absence of substrates and substrate analogs. The crystal structures of a series of complexes may then be solved by molecular replacement and compared to that of the wild-type isomerase to assist in determination of suitable replacements for R-groups within the active site, thus making isomerase mutants according to the present invention.

All mutants of the present inventions may be modeled using the information disclosed herein without necessarily having to crystallize and solve the structure for each and every mutant. For example, one skilled in the art may use one of several specialized computer programs to assist in the process of designing isomerases having mutated active sites relative to the wild-type isomerase. Examples of such programs include: GRID (Goodford, 1985, J. Mod. Chem., 28:849-857), MCSS (Miranker and Karplus, 1991, Proteins: Structure, Function and Genetics, 11:29-34); AUTODOCK (Goodsell and Olsen, 1990, Proteins. Structure, Fumtion, and Genetics, 8:195-202); and DOCK (Kuntz et al., 1982, J. Mot BioL, 161:269-288), and the like, as well as those discussed in the Examples below. In addition, specific computer programs are also available to evaluate specific substrate-active site interactions and the deformation energies and electrostatic interactions resulting therefrom. MODELLER is a computer program often used for homology or comparative modeling of the three-dimensional structure of a protein. A. Saii & T. L. Blundell. J. Mol. Biol. 234:779-815, 1993. A sequence to be modeled is aligned with one or more known related structures and the MODELLER program is used to calculate a full-atom model, based on optimum satisfaction of spatial restraints. Such restraints can include, inter alia, homologous structures, site-directed mutagenesis, fluorescence spectroscopy, NMR experiments, or atom-atom potentials of mean force.

The present invention enables isomerase mutants to be made and the crystal structure thereof to be solved. Moreover, by virtue of the present invention, the location of the active site and the interface of substrate therewith permit the identification of desirable R-groups for introduction by mutagenesis.

The three-dimensional coordinates of the isomerases provided herein may additionally be used to predict the activity and or substrate specificity of a protein whose primary amino acid sequence suggests that it may have isomerase activity. The family of CHI-related enzymes is defined, in part, by a number of conserved amino acid residues including, for example, residues spanning β3a, β3b, α4, and α6 in the three-dimensional structure. By employing the three-dimensional coordinates disclosed herein and computer modeling programs, structural comparisons of CHI can be made with a putative enzyme. Differences between the two would provide the skilled artisan with information regarding the activity and/or substrate specificity of the putative enzyme.

Thus, in another embodiment of the invention, there is provided a method of predicting the activity and/or substrate specificity of an isomerase or putative isomerase comprising (a) generating a three-dimensional representation of a known isomerase (e.g., chalcone isomerase) using three-dimensional coordinate data, (b) generating a predicted three-dimensional representation of a putative isomerase, and (c) comparing the representation of the known isomerase with the representation of the putative isomerase, wherein the differences between the two representations are predictive of activity and/or substrate specificity of the putative isomerase.

In a further embodiment of the present invention, there is also provided a method of identifying a potential substrate of an isomerase comprising (a) defining the active site of an isomerase (e.g., chalcone isomerase) based on the atomic coordinates of the isomerase, (b) identifying a potential substrate that fits the defined active site, and (c) contacting the isomerase with the potential substrate of (b) and determining the activity thereon. Techniques for computer modeling and structural comparisons similar to those described herein for predicting putative isomerase activity and/or substrate specificity can be used to identify novel substrates for isomerases. The plurality of atomic coordinates that can be used to define the active site of an isomerase include those set forth in PDB Accession Nos: 1EYP (SEQ ID NOs:9-11), 1EYQ (SEQ ID NO:9), 1FM7 (SEQ ID NO:9), 1FM8 (SEQ ID NO:9), 1JEP (SEQ ID NO:9) and Table 1 (SEQ ID NOs:9-11). A subset or portion of these atomic coordinates can also be used, for example, those atomic coordinates defining the amino acid residues which comprise the enzymatic active site.

In addition, the structural coordinates and three-dimensional models disclosed herein can be used to design or identify isomerase inhibitors. Using the modeling techniques disclosed herein, potential inhibitor structures can be modeled with the isomerase active site and those that appear to interact therewith can subsequently be tested in activity assays in the presence of substrate.

Methods of using crystal structure data to design binding agents or substrates are known in the art. Thus, the crystal structure data provided herein can be used in the design of new or improved inhibitors, substrates or binding agents. For example, the isomerase polypeptide coordinates can be superimposed onto other available coordinates of similar enzymes to identify modifications in the active sites of the enzymes to create novel by-products of enzymatic activity or to modulate flavonoid synthesis. Alternatively, the isomerase polypeptide coordinates can be superimposed onto other available coordinates of similar enzymes which have substrates or inhibitors bound to them to give an approximation of the way these and related substrates or inhibitors might bind to an isomerase. Alternatively, computer programs employed in the practice of rational drug design can be used to identify compounds that reproduce interaction characteristics similar to those found between a isomerase polypeptide and a co-crystallized substrate. Furthermore, detailed knowledge of the nature of binding site interactions allows for the modification of compounds to alter or improve solubility, pharmacokinetics, etc. without affecting binding activity.

Computer programs are widely available that are capable of carrying out the activities necessary to design agents using the crystal structure information provided herein. Examples include, but are not limited to, the computer programs listed below:

-   -   CATALYST DATABASES™—an information retrieval program accessing         chemical databases such as BioByte Master File, Derwent WDI and         ACD;     -   CATALYST/HYPO™—generates models of compounds and hypotheses to         explain variations of activity with the structure of drug         candidates;     -   LUDI™—fits molecules into the active site of a protein by         identifying and matching complementary polar and hydrophobic         groups;     -   LEAPFROG™—“grows” new ligands using a genetic algorithm with         parameters under the control of the user.

In addition, various general purpose machines may be used with programs written in accordance with the teachings herein, or it may be more convenient to construct more specialized apparatus to perform the operations. However, preferably the embodiment is implemented in one or more computer programs executing on programmable systems each comprising at least one processor, at least one data storage system (including volatile and non-volatile memory and/or storage elements), at least one input device, and at least one output device. The program is executed on the processor to perform the functions described herein.

Each such program may be implemented in any desired computer language (including machine, assembly, high level procedural, object oriented programming languages, or the like) to communicate with a computer system. In any case, the language may be a compiled or interpreted language. The computer program will typically be stored on a storage media or device (e.g., ROM, CD-ROM, or magnetic or optical media) readable by a general or special purpose programmable computer, for configuring and operating the computer when the storage media or device is read by the computer to perform the procedures described herein. The system may also be considered to be implemented as a computer-readable storage medium, configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein.

Embodiments of the invention include systems (e.g., interne based systems), particularly computer systems which store and manipulate the coordinate and sequence information described herein. One example of a computer system 100 is illustrated in block diagram form in FIG. 5. As used herein, “a computer system” refers to the hardware components, software components, and data storage components used to analyze the coordinates and sequences as set forth in Accession Nos. 1EYP (SEQ ID NOs:9-11), 1EYQ (SEQ ID NO:9), 1FM7 (SEQ ID NO:9), 1FM8 (SEQ ID NO:9), and Table 1 (SEQ ID NOs:9-11). The computer system 100 typically includes a processor for processing, accessing and manipulating the sequence data. The processor 105 can be any well-known type of central processing unit, such as, for example, the Pentium III from Intel Corporation, or similar processor from Sun, Motorola, Compaq, AMD or International Business Machines.

Typically the computer system 100 is a general purpose system that comprises the processor 105 and one or more internal data storage components 110 for storing data, and one or more data retrieving devices for retrieving the data stored on the data storage components. A skilled artisan can readily appreciate that any one of the currently available computer systems are suitable.

In one particular embodiment, the computer system 100 includes a processor 105 connected to a bus which is connected to a main memory 115 (preferably implemented as RAM) and one or more internal data storage devices 110, such as a hard drive and/or other computer readable media having data recorded thereon. In some embodiments, the computer system 100 further includes one or more data retrieving device 118 for reading the data stored on the internal data storage devices 110.

The data retrieving device 118 may represent, for example, a floppy disk drive, a compact disk drive, a magnetic tape drive, or a modem capable of connection to a remote data storage system (e.g., via the internet) etc. In some embodiments, the internal data storage device 110 is a removable computer readable medium such as a floppy disk, a compact disk, a magnetic tape, etc. containing control logic and/or data recorded thereon. The computer system 100 may advantageously include or be programmed by appropriate software for reading the control logic and/or the data from the data storage component once inserted in the data retrieving device.

The computer system 100 includes a display 120 which is used to display output to a computer user. It should also be noted that the computer system 100 can be linked to other computer systems 125 a-c in a network or wide area network to provide centralized access to the computer system 100.

Software for accessing and processing the coordinate and sequences described herein, (such as search tools, compare tools, and modeling tools etc.) may reside in main memory 115 during execution.

For the first time, the present invention permits the use of molecular design techniques to design, select and synthesize novel enzymes, chemical entities and compounds, including inhibitory compounds, capable of binding to an isomerase polypeptide (e.g., a chalcone isomerase polypeptide), in whole or in part.

One approach enabled by this invention, is to use the structural coordinates as set forth in Accession Nos. 1EYP (SEQ ID NOs:9-11), 1EYQ (SEQ ID NO:9), 1FM7 (SEQ ID NO:9), 1FM8 (SEQ ID NO:9), 1JEP (SEQ ID NO:9), and Table 1 (SEQ ID NOs:9-11) to design new enzymes capable of synthesizing novel flavonoids. For example, isomerases generate molecular diversity in their products by utilizing different starter molecules. The structural coordinates disclosed herein allow the elucidation of the nature by which isomerases achieve starter molecule selectivity and control flavonoid diversity and synthesis. Accordingly, the invention allows for the strategic development and biosynthesis of more diverse flavonoids and demonstrates a structural basis for control of flavonoid synthesis. In addition, the structural coordinates allow for the development of substrates or binding agents that bind to the polypeptide and alter the physical properties of the compounds in different ways, e.g., solubility.

In another approach an isomerase polypeptide crystal is probed with molecules composed of a variety of different chemical entities to determine optimal sites for interaction between candidate binding molecules (e.g., substrates) and the isomerase (e.g., chalcone isomerase).

In another embodiment, an approach made possible and enabled by this invention, is to screen computationally small molecule data bases for chemical entities or compounds that can bind in whole, or in part, to an isomerase polypeptide or fragment thereof. In this screening, the quality of fit of such entities or compounds to the binding site may be judged either by shape complementarity or by estimated interaction energy. Meng, E. C. et al., J. Comp. Chem, 13, pp. 505-524 (1992).

Chalcone isomerase is one member of a family of isomerase polypeptides, many of which have similar functional activity. In addition, many isomerase polypeptides may crystallize in more than one crystal form. Accordingly, the structural coordinates of chalcone isomerase, or portions thereof, as provided by this invention are particularly useful to solve the structure, function or activity of other crystal forms of isomerase polypeptides. They may also be used to solve the structure of an isomerase or a chalcone isomerase mutant.

One method that may be employed for this purpose is molecular replacement. In this method, the unknown crystal structure, whether it is another isomerase crystal form, chalcone isomerase, chalcone isomerase mutant, an isomerase complexed with a substrate or other molecule, or the crystal of some other protein with significant amino acid sequence homology to any isomerase polypeptide, may be determined using the structure coordinates as provided in Accession Nos. 1EYP (SEQ ID NOs:9-11), 1EYQ (SEQ ID NO:9), 1FM7 (SEQ ID NO:9), 1FM8 (SEQ ID NO:9), 1JEP (SEQ ID NO:9) and Table 1 (SEQ ID NOs:9-11). This method will provide an accurate structural form for the unknown crystal more quickly and efficiently than attempting to determine such information ab initio.

In addition, in accordance with the present invention, an isomerase, chalcone isomerase or chalcone isomerase mutant may be crystallized in association or complex with known isomerase binding agents, substrates, or inhibitors. The crystal structures of a series of such complexes may then be solved by molecular replacement and compared with that of wild-type isomerase polypeptides. Potential sites for modification within the isomerase polypeptide may thus be identified. This information provides an additional tool for determining the most efficient binding interactions between an isomerase and a chemical entity, substrate or compound.

All of the complexes referred to above may be studied using well-known X-ray diffraction techniques and may be refined to 2-3 Å resolution X-ray data to an R value of about 0.20 or less using computer software, such as X-PLOR (ale University, 1992, distributed by Molecular Simulations, Inc.). See, e.g., Blundel & Johnson, supra; Methods in Enzymology, vol. 114 and 115, H. W. Wyckoff et al., eds., Academic Press (1985). This information may thus be used to optimize known classes of isomerase substrates or binding agents (e.g., inhibitors), and to design and synthesize novel classes of isomerases, substrates, and binding agents (e.g., inhibitors).

The design of substrates, compounds or binding agents that bind to or inhibit a chalcone isomerase polypeptide according to the invention generally involves consideration of two factors. First, the substrate, compound or binding agent must be capable of physically and structurally associating with the isomerase polypeptide. Non-covalent molecular interactions important in the association of a polyketide isomerase with a substrate include hydrogen bonding, van der Waals and hydrophobic interactions, and the like.

Second, the substrate, compound or binding agent must be able to assume a conformation that allows it to associate with an isomerase polypeptide. Although certain portions of the substrate, compound or binding agent will not directly participate in this association, those portions may still influence the overall conformation of the molecule. This, in turn, may have a significant impact on potency. Such conformational requirements include the overall three-dimensional structure and orientation of the chemical entity or compound in relation to all or a portion of the binding site, e.g., active site or accessory binding site of a polyketide isomerase (e.g., a chalcone isomerase polypeptide), or the spacing between functional groups of a substrate or compound comprising several chemical entities that directly interact with an isomerase.

The potential binding effect of a substrate or chemical compound on an isomerase or the activity of a newly synthesized or mutated isomerase might have on a known substrate may be analyzed prior to its actual synthesis and testing by the use of computer modeling techniques. For example, if the theoretical structure of the given substrate or compound suggests insufficient interaction and association between it and an isomerase, synthesis and testing of the compound may not be warranted. However, if computer modeling indicates a strong interaction, the molecule may then be tested for its ability to bind to, initiate catalysis or elongation of a flavonoid by an isomerase. Methods of assaying for isomerase activity are known in the art (as identified and discussed herein). Methods for assaying the effect of a newly created isomerase or a potential substrate or binding agent can be performed in the presence of a known binding agent or isomerase. For example, the effect of the potential binding agent can be assayed by measuring the ability of the potential binding agent to compete with a known substrate.

A mutagenized isomerase, novel isomerase, substrate or other binding compound of an isomerase may be computationally evaluated and designed by means of a series of steps in which chemical entities or fragments are screened and selected for their ability to associate with the individual binding pockets or other areas of the isomerase.

One skilled in the art may use one of several methods to screen chemical entities or fragments for their ability to associate with an isomerase and more particularly with the individual binding pockets of a chalcone isomerase polypeptide. This process may begin by visual inspection of, for example, the active site on the computer screen based on the coordinates in Accession Nos. 1EYP (SEQ ID NOs:9-11), 1EYQ (SEQ ID NO:9), 1FM7 (SEQ ID NO:9), 1FM8 (SEQ ID NO:9), and Table 1 (SEQ ID NOs:9-11). Selected fragments or substrates or chemical entities may then be positioned in a variety of orientations, or docked, within an individual binding pocket of an isomerase. Docking may be accomplished using software such as QUANTA and SYBYL, followed by energy minimization and molecular dynamics with standard molecular mechanics forcefields, such as CHARMM and AMBER.

Specialized computer programs may also assist in the process of selecting fragments or chemical entities. These include:

1. GRID (Goodford, P. J., “A Computational Procedure for Determining Energetically Favorable Binding Sites on Biologically Important Macromolecules”, J. Med. Chem., 28, pp. 849-857 (1985)). GRID is available from Oxford University, Oxford, UK.

2. MCSS (Miranker, A. and M. Karplus, “Functionality Maps of Binding Sites: A Multiple Copy Simultaneous Search Method.” Proteins: Structure. Function and Genetics, 11, pp. 29-34 (1991)). MCSS is available from Molecular Simulations, Burlington, Mass.

3. AUTODOCK (Goodsell, D. S. and A. J. Olsen, “Automated Docking of Substrates to Proteins by Simulated Annealing”, Proteins: Structure. Function, and Genetics, 8, pp. 195-202 (1990)). AUTODOCK is available from Scripps Research Institute, La Jolla, Calif.

4. DOCK (Kuntz, I. D. et al., “A Geometric Approach to Macromolecule-Ligand Interactions”, J. Mol. Biol., 161, pp. 269-288 (1982)). DOCK is available from University of California, San Francisco, Calif.

Once suitable substrates, chemical entities or fragments have been selected, they can be assembled into a single polypeptide, compound or binding agent (e.g., an inhibitor). Assembly may be performed by visual inspection of the relationship of the fragments to each other on the three-dimensional image displayed on a computer screen in relation to the structure coordinates of the molecules as set forth in Accession Nos. 1EYP (SEQ ID NOs:9-11), 1EYQ (SEQ ID NO:9), 1FM7 (SEQ ID NO:9), 1FM8 (SEQ ID NO:9), and Table 1 (SEQ ID NOs:9-11). This would be followed by manual model building using software such as QUANTA or SYBYL.

Useful programs to aid one of skill in the art in connecting the individual chemical entities or fragments include:

1. CAVEAT (Bartlett, P. A. et al, “CAVEAT: A Program to Facilitate the Structure-Derived Design of Biologically Active Molecules”. In “Molecular Recognition in Chemical and Biological Problems”, Special Pub., Royal Chem. Soc., 78, pp. 182-196 (1989)). CAVEAT is available from the University of California, Berkeley, Calif.

2. 3D Database systems such as MACCS-3D (MDL Information Systems, San Leandro, Calif.). This area is reviewed in Martin, Y. C., “3D Database Searching in Drug Design”, J. Med. Chem., 35, pp. 2145-2154 (1992)).

3. HOOK (available from Molecular Simulations, Burlington, Mass.).

In addition to the method of building or identifying novel enzymes or an isomerase substrate or binding agent in a step-wise fashion one fragment or chemical entity at a time as described above, substrates, inhibitors or other isomerase interactions may be designed as a whole or “de novo” using either an empty active site or optionally including some portion(s) of known substrates, binding agents or inhibitors. These methods include:

1. LUDI (Bohm, H.-J., “The Computer Program LUDI: A New Method for the De Novo Design of Enzyme Inhibitors”, J. Comp. Aid. Molec. Design, 6, pp. 61-78 (1992)). LUDI is available from Biosym Technologies, San Diego, Calif.

2. LEGEND (Nishibata, Y. and A. Itai, Tetrahedron, 47, p. 8985 (1991)). LEGEND is available from Molecular Simulations, Burlington, Mass.

3. LEAPFROG (available from Tripos Associates, St. Louis, Mo.).

Other molecular modeling techniques may also be employed in accordance with this invention. See, e.g., Cohen, N. C. et al., “Molecular Modeling Software and Methods for Medicinal Chemistry”, J. Med. Chem., 33, pp. 883-894 (1990). See also, Navia, M. A. and M. A. Murcko, “The Use of Structural Information in Drug Design”, Current Opinions in Structural Biology, 2, pp. 202-210 (1992).

Once a substrate, compound or binding agent has been designed or selected by the above methods, the efficiency with which that substrate, compound or binding agent may bind to an isomerase may be tested and optimized by computational evaluation.

A substrate or compound designed or selected as an isomerase binding agent may be further computationally optimized so that in its bound state it would preferably lack repulsive electrostatic interaction with the target site. Such non-complementary (e.g., electrostatic) interactions include repulsive charge-charge, dipole-dipole and charge-dipole interactions. Specifically, the sum of all electrostatic interactions between the binding agent and the isomerase when the binding agent is bound to the isomerase, preferably make a neutral or favorable contribution to the enthalpy of binding.

Specific computer software is available in the art to evaluate compound deformation energy and electrostatic interaction. Examples of programs designed for such uses include: GAUSSIAN 92, revision C (M. J. Frisch, Gaussian, Inc., Pittsburgh, Pa., 1992); AMBER, version 4.0 (P. A. Kollman, University of California at San Francisco, 1994); QUANTA/CHARMM (Molecular Simulations, Inc., Burlington, Mass. 1994); and INSIGHT II/DISCOVER (Biosysm Technologies Inc., San Diego, Calif., 1994). These programs may be implemented, for example, using a Silicon Graphics workstation, IRIS 4D/35 or IBM RISC/6000 workstation model 550. Other hardware systems and software packages will be known to those skilled in the art of which the speed and capacity are continually modified.

Once an isomerase, isomerase substrate or isomerase binding agent has been selected or designed, as described above, substitutions may then be made in some of its atoms or side groups in order to improve or modify its binding properties. Generally, initial substitutions are conservative, e.g., the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original group. Such substituted chemical compounds may then be analyzed for efficiency of fit to a polyketide isomerase substrate or fit of a modified substrate to an isomerase having a structure defined by the coordinates in Accession Nos. 1EYP (SEQ ID NOs:9-11), 1EYQ (SEQ ID NO:9), 1FM7 (SEQ ID NO:9), 1FM8 (SEQ ID NO:9), 1JEP (SEQ ID NO:9) and Table 1 (SEQ ID NOs:9-11), by the same computer methods described, above.

Conserved regions of the flavonoid family isomerases lend themselves to the methods and compositions of the invention. For example, a number of isomerases have conserved residues present within their active sites (as described more fully below). Accordingly, modification to the active site of chalcone isomerase or a chalcone isomerase substrate can be extrapolated to other conserved members of the family of isomerases.

Functional fragments of isomerase polypeptides such as, for example, fragments of chalcone isomerase, can be designed based on the crystal structure and atomic coordinates described herein. Fragments of a chalcone isomerase polypeptide and the fragment's corresponding atomic coordinates can be used in the modeling described herein. In addition, such fragments may be used to design novel substrates or modified active sites to create new diverse flavonoids.

In one embodiment of the present invention, the crystal structure and atomic coordinates allow for the design of novel isomerases and novel isomerase substrates. The development of new isomerases will lead to the development a biodiverse library of flavonoids for use as therapeutics (e.g., as antibiotics, anti-cancer agents, anti-fungal agents) as described herein or known in the art. In vitro assay systems for production and determination of activity are known in the art. For example, antibiotic activities of novel products of the polyketide pathway and flavonoid pathway can be measured by any number of anti-microbial techniques currently used in hospitals and laboratories. In addition, anticancer activity can be determined by contacting cells having a cell proliferative disorder with a newly synthesized flavonoid and measuring the proliferation or apoptosis of the cells before and after contact with the flavonoid. Specific examples of apoptosis assays are provided in the following references: Lymphocyte: C. J. Li et al., Science, 268:429-431, 1995; D. Gibellini et al., Br. J. Haematol. 89:24-33, 1995; S. J. Martin et al., J. Immunol. 152:330-42, 1994; C. Terai et al., J. Clin Invest. 87:1710-5, 1991; J. Dhein et al., Nature 373:438-441, 1995; P. D. Katsikis et al., J. Exp. Med. 1815:2029-2036, 1995; Michael O. Westendorp et al., Nature 375:497, 1995; DeRossi et al., Virology 198:234-44, 1994. Fibroblasts: H. Vossbeck et al., Int. J. Cancer 61:92-97, 1995; S. Goruppi et al., Oncogene 9:1537-44, 1994; A. Fernandez et al., Oncogene 9:2009-17, 1994; E. A. Harrington et al., Embo J. 13:3286-3295, 1994; N. Itoh et al., J. Biol. Chem. 268:10932-7, 1993. Neuronal Cells: G. Melino et al., Mol. Cell. Biol. 14:6584-6596, 1994; D. M. Rosenbaum et al., Ann. Neurol. 36:864-870, 1994; N. Sato et al., J. Neurobiol 25:1227-1234, 1994; G. Ferrari et al., J. Neurosci. 1516:2857-2866, 1995; A. K. Talley et al., Mol. Cell Biol. 1585:2359-2366, 1995; A. K. Talley et al., Mol. and Cell. Biol. 15:2359-2366, 1995; G. Walkinshaw et al., J. Clin. Invest. 95:2458-2464, 1995. Insect Cells: R. J. Clem et al., Science 254:1388-90, 1991; N. E. Crook et al., J. Virol. 67:2168-74, 1993; S. Rabizadeh et al., J. Neurochem. 61:2318-21, 1993; M. J. Birnbaum et al., J. Virol 68:2521-8, 1994; R. J. Clem et al., Mol. Cell. Biol. 14:5212-5222, (1994). Other assays are well within the ability of those of skill in the art.

Production of novel flavonoids or isomerases can be carried out in culture. For example, mammalian expression constructs carrying isomerases can be introduced into various cell lines such as CHO, 3T3, HL60, Rat-1, or Jurkart cells, for example. In addition, SF21 insect cells may be used in which case the isomerase gene is expressed using an insect heat shock promoter.

In another embodiment of the present invention, once a novel substrate or binding agent is developed by the computer methodology discussed above, the invention provides a method for determining the ability of the substrate or agent to be acted upon by an isomerase. The method includes contacting components comprising the substrate or agent and an isomerase, or a recombinant cell expressing an isomerase, under conditions sufficient to allow the substrate or agent to interact and determining the affect of the agent on the activity of the polypeptide. The term “affect”, as used herein, encompasses any means by which protein activity can be modulated, and includes measuring the interaction of the agent with the isomerase polypeptide by physical means including, for example, fluorescence detection of the binding of an agent to the polypeptide. Such agents can include, for example, polypeptides, peptidomimetics, chemical compounds, small molecules, substrates and biologic agents as described herein. Examples of small molecules include but are not limited to small peptides or peptide-like molecules.

Contacting or incubating includes conditions which allow contact between the test agent or substrate and an isomerase or modified isomerase polypeptide or a cell expressing an isomerase or modified isomerase polypeptide. Contacting includes in solution and in solid phase. The substrate or test agent may optionally be a combinatorial library for screening a plurality of substrates or test agents. Agents identified in the method of the invention can be further evaluated by chromatography, cloning, sequencing, and the like.

In yet another embodiment, the present invention provides a computer for producing a three-dimensional representation of a molecule or molecular complex or a homologue of said molecule or molecular complex, wherein said molecule or molecular complex or a homologue of said molecule or molecular complex comprises an active site defined by atomic coordinates are as set forth in PDB Accession Nos: 1EYP (SEQ ID NOs:9-11), 1EYQ (SEQ ID NO:9), 1FM7 (SEQ ID NO:9), 1FM8 (SEQ ID NO:9), 1JEP (SEQ ID NO:9), or Table 1 (SEQ ID NOs:9-11), wherein said computer comprises:

-   -   i) a computer-readable data storage medium comprising a data         storage material encoded with computer-readable data, wherein         said data comprises atomic coordinates are as set forth in PDB         Accession Nos: 1EYP, 1EYQ, 1FM7, 1FM8, 1JEP, or Table 1;     -   (ii) a working memory for storing instructions for processing         said computer-readable data;     -   (iii) a central-processing unit coupled to said working memory         and to said computer-readable data storage medium for processing         said computer-machine readable data into said three-dimensional         representation; and     -   (iv) a display coupled to said central-processing unit for         displaying said three-dimensional representation.

Such a computer could also be used to determine at least a portion of the atomic coordinates corresponding to X-ray diffraction data obtained from a molecule or molecular complex or a homologue of said molecule or molecular complex.

In yet another embodiment, the present invention provides methods of screening compounds to determine whether they are isomerase substrates, said method comprising:

-   -   a) determining the points of interaction between an isomerase         and a substrate or product therefor;     -   b) selecting compound(s) having similar interaction with said         isomerase; and     -   c) testing the selected compound for the ability to be converted         by said isomerase.

An alternative method of screening compounds to determine whether they are isomerase substrates comprises:

-   -   a) selecting compound(s) having points of interaction with said         isomerase, wherein similar points of interaction have been         determined between said isomerase and a substrate or product         therefor; and     -   b) testing the selected compound for the ability to be converted         by said isomerase.

Another alternative method of screening compounds to determine whether they are isomerase substrates comprises:

-   -   testing a compound for the ability to be converted by said         isomerase,     -   wherein said compound has been selected as having points of         interaction with said isomerase, and     -   wherein similar points of interaction have been determined         between said isomerase and a substrate or product therefor.

In another embodiment, the present invention provides methods for screening for compounds that inhibit an isomerase comprising:

-   -   a) determining the points of interaction between an isomerase         and a substrate or product therefor;     -   b) selecting compound(s) having similar interaction with said         isomerase; and     -   c) testing the selected compound for the ability to inhibit the         activity of said isomerase.

An alternative method for screening for compounds that inhibit an isomerase comprises:

-   -   a) selecting compound(s) having points of interaction with an         isomerase, wherein similar points of interaction have been         determined between said isomerase and a substrate or product         therefor; and     -   b) testing the selected compound for the ability to inhibit the         activity of said isomerase.

Another alternative method for screening for compounds that inhibit an isomerase comprises:

-   -   testing a compound for the ability to inhibit the activity of         said isomerase,     -   wherein said compound has been selected as having points of         interaction with said isomerase, and     -   wherein similar points of interaction have been determined         between said isomerase and a substrate or product therefor.

The present invention also claims a compound identified by these methods and a composition comprising such a compound and an acceptable carrier therefor.

Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The invention will now be described in greater detail by reference to the following non-limiting examples.

EXAMPLES Expression, Mutagenesis, and Purification

Alfalfa CHI (SEQ ID NO:1) cDNA was PCR amplified and inserted into the pHIS8 expression vector (Jez et al., Biochemistry 39:890-902, 2000). The CHI Y106F mutant (SEQ ID NO:13) was generated with the QuikChange (Stratagene) PCR method. N-terminal His-tagged protein was expressed in E. coli BL21(DE3) cells. Tagged CHI was purified from sonicates using a Ni²⁺-NTA (Qiagen) column. Thrombin digestion removed the histidine tag, and the protein was passed over a Ni²⁺-NTA column. Digested CHI was depleted of thrombin using a benzamidine-Sepharose column. Gel filtration on a SUPERDEX-75 (Pharmacia) FPLC column was the final purification step.

Enzyme Assays

CHI assays were performed at 25° C. in a 0.5 ml reaction volume containing 0.05 M Hepes (pH 7.5), 50 μM 6′-deoxychalcone, and 3% ethanol as co-solvent. Time-dependent decreases in 6′-deoxychalcone absorbance (λ_(max)=390 nm; ε=29,400 M⁻¹ cm⁻¹) were monitored with a Beckman DU-640 spectrophotometer. Determination of steady-state kinetic constants used the standard assay system with varied concentrations of substrate (2-50 μM) following fitting to the Michaelis-Menton equation using KALEIDAGRAPH (Abelbeck Software).

Crystallization, Structure Determination, and Refinement of the Native Structure

Crystals of CHI (SEQ ID NO:1) were grown at 4° C. by vapor diffusion using the hanging drop method. A 2 μl drop containing a 1:1 mixture of 25 mg ml⁻¹ CHI and crystallization buffer (25% glycerol, 1.8-2.0 M ammonium sulfate and 0.05 M PIPES, pH 6.5) yielded diffraction quality crystals within a few days at 4° C. Crystals grew in space group P6₅22 with unit cell dimensions of a=90.37 Å; c=352.86 Å with two molecules per asymmetric unit and a solvent content of 72%. Native CHI diffraction data (105 K) were collected at beamline 7-1 of the Stanford Synchrotron Radiation Source (SSRL 7-1) on a 30 cm MAR imaging plate system. For generation of heavy atom derivatives, CHI crystals were soaked in mother liquor with either 1.2 mM K₂OsCl₆ or 1 mM HgCl₂ for 12-16 hours. Heavy atom data (105 K) were collected at SSRL 9-1 on a 30 cm MAR imaging plate system. All images were indexed and integrated using DENZO and the reflections merged with SCALEPACK (Otwinowski, Z. & Minor, W., Methods Enzymol. 276:307-326, 1997). Data reduction was completed using programs from CCP4 (Collaborative Computational Project 4 (CCP4) Acta Crystallogr. D53:240-255, 1994) (See Table 3). Heavy atom sites were located with SOLVE (Terwilliger, T. C. & Berendzen, J. Acta Crystallogr. D55:849-861, 1999) Refinement of sites and location of additional sites used MLPHARE (Otwinowski, Z. ML-PHARE in Daresbary Study Weekend Proceedings (CCP4, SERC Daresbary Laboratory, Warrington, UK; 1991). SHARP was used for phase calculation and heavy atom refinement (de La Fortelle, E. & Bricogne, G. Methods Enzymol. 276:472-494, 1997). This set of experimental phases was improved and extended using solvent flipping with SOLOMON (Abrahams, J. P. & Leslie, A. G. W. Acta Crystallogr. D52:30-42, 1996). Model building was performed with 0. CNS was used for refinement (Brünger, A. T. et al. Acta Crystallogr. D54:905-921, 1998). The initial model was subjected to simulated annealing, positional refinement, and group B-factor refinement with strict non-crystallographic symmetry maintained between both molecules in the asymmetric unit. In subsequent rounds of model building and refinement, non-crystallographic constraints were released and water molecules were added using CNS to yield the R-factors shown in Table 3. The final model included residues 4 to 215 of monomer A (SEQ ID NO:9), residues 3 to 38 (SEQ ID NO:10) and 45 to 215 (SEQ ID NO:11) of monomer B. The quality of the CHI model was checked with PROCHECK (Laskowski, R. A., MacArthur, M. W., Moss, D. S., & Thornton, J. M. J. Appl. Crystallogr. 26:283-291, 1993). A total of 89.6% of the residues in CHI are in the most favored regions of the Ramachandran plot and 10.4% are in the additional allowed region.

Overall Structure

Expression of alfalfa CHI (SEQ ID NO:1) in E. coli yielded active enzyme that was purified and crystallized. The overall structure of CHI resembles an upside-down bouquet that adopts an open-faced β-sandwich fold (FIGS. 1B and 1C). A large β-sheet β3a-β3f) and a layer of α-helices (α1-α7) comprise the core structure with three short β-strands (β1a, β1b, β2) on the opposite side of the large β-sheet. A search of the Protein Data Bank using DALI revealed no other structurally homologous folds. In addition, a PSI-BLAST search of sequence databases showed that CHI-like sequences are currently found typically in plants and these sequences display no detectable homology with other proteins. These results imply that the CHI three-dimensional fold and enzymatic activity are typically found in the plant kingdom. Amino acid sequence comparison of CHIs from a variety of advanced land plants reveals high homology (49% to 82% amino acid sequence identity) with regions of conservation spread uniformly throughout the primary structure (FIG. 1D, SEQ ID NOs:1-8). Interestingly, there is conservation of residues spanning β3a, β3b, α4, and α6 in the three-dimensional structure among CHIs from different species. Notably, these structural elements form the active site on the protein surface.

Accumulating data suggests that co-localization of proteins in loosely associated macromolecular complexes is a fundamental component of cellular processes, including flavonoid biosynthesis. CHI and other flavonoid biosynthetic enzymes may associate to provide efficient channeling of substrates and products as shown recently in Arabidopsis thaliana. Although the three short β-strands (β1a, β1b, β2) on the backside of the CHI structure form a relatively flat surface that would be ideal for protein-protein interactions, both gel filtration and analytical ultracentrifugation experiments failed to detect association of alfalfa CHI (SEQ ID NO:1) and alfalfa chalcone synthase 2 in vitro.

TABLE 3 Crystallographic data, phasing, and refinement information Native K₂OsCl₆ HgCl₂ Naringenin Wavelength (Å) 1.08 0.98 0.98 0.95 Resolution range (Å) 38.1-2.50 78.0-3.24 76.0-3.26 46.7-1.85 Observations 86,781 44,070 39,193 697,121 Unique reflections 27,863 24,966 22,238 70,889 Completeness¹ (%) 90.7 (61.7) 99.2 (99.6) 95.8 (98.2) 85.5 (60.6) I/□¹ 19.4 (2.0)  9.3 (2.6) 17.5 (7.4)  28.0 (2.0)  R_(sym) ^(1,2) (%)  5.4 (36.5) 10.3 (31.2)  5.8 (12.0)  4.8 (45.4) POP³ (acentric/centric) 2.55/1.85 1.58/1.07 R_(cullis) ⁴ (iso/ano) 0.52/0.76 0.72/0.81 R_(cryst) ⁵/R_(free) ⁶ (%) 24.9/28.0 23.7/26.2 Protein atoms 3181 3222 Water molecules 94 382 Ligand atoms⁷ 40 nar/20 sul R.m.s.d. bonds (Å) 0.019 0.019 R.m.s.d. angles (°) 2.0 2.1 average B-factor - protein (Å²) 60.6 46.8 average B-factor - water (Å²) 62.7 50.1 ¹Number in parenthesis is for highest resolution shell; ²R_(sym) = Σ|I_(h) − <I_(h)>|/ ΣI_(h), where <I_(h)>, is the average intensity over symmetry equivalent reflections; ³Power of Phasing = <|F_(H(calc))/|E|>, where F_(H(calc))is the calculated difference and E is the lack of closure; ⁴R_(cullis) = Σ|E|/Σ|F_(PH) − F_(P)|; ⁵R-factor = Σ|F_(obs) − F_(calc)|/ΣF_(obs), where summation is over the data used for refinement; ⁶R_(free)-factor was calculated using 5% of data excluded from refinement; ⁷nar = naringenin and sul = sulfate. Crystallization, Structure Determination, and Refinement of the CHI•Naringenin Complex Structure

Crystals of the CHI•naringenin (SEQ ID NO:5) complex (P6₅22; a=89.47 Å; c=351.19 Å) (and other co-complexes) were grown as above from a crystallization buffer containing 2.5 mM (2S/2R)-naringenin and 5% ethanol. Data (105 K) were collected at SSRL 9-2 with a Quantum 4 CCD detector. Images were processed as above. Following rigid-body refinement with CNS, electron density resembling naringenin was observed in each monomer and modeled as such. In subsequent rounds of refinement and rebuilding, the R-factors converged to those listed in Table 3. The final model includes residues 4 to 215 of both monomers.

(2S)-Naringenin Binding and Reaction Stereoselectivity

The location of (2S)-naringenin in the CHI (SEQ ID NO:5) structure defines the active site (FIG. 2). Although a commercially obtained mixture of (2S)- and (2R)-naringenin was used for co-crystallization, only the (2S)-isomer bound the CHI active site. The position of the (2S)-naringenin binding cleft is consistent with inactivation studies that suggested a cysteine residue (Cys 114 in alfalfa CHI, SEQ ID NO:1) is proximal to the active site. In the CHI structure, Cys 114 is near the binding cleft but does not directly contact (2S)-naringenin. The active site cleft is largely apolar and consists of residues from β3a (Arg 36, Gly 37, Leu 38), β3b (Phe 47, Thr 48, Ile 50), α4 (Tyr 106, Lys 109, Val 110, Asn 113), and α6 (Thr 190, Met 191) (FIG. 2B) (SEQ ID NO:9). The apolar methylene carbons of Arg 36 (SEQ ID NO:9) are positioned by a restraining charge-charge interaction from the 8-guanido group to Glu 200. In addition, the methylene carbons of Lys 109 (SEQ ID NO:9) are fixed by a charge-charge interaction between the side chain amine and Glu 112. Except for Thr 190 and Met 191, the residues contacting (2S)-naringenin are identical among CHIs from different plants (FIG. 1D) (SEQ ID NOs:1-8). Although van der Waals contacts dominate the interactions between CHI and (2S)-naringenin, two hydrogen bond interactions exist. The first is mediated by the side chain hydroxyl moiety of Thr 48 bound to the 4′-hydroxyl group of (2S)-naringenin (SEQ ID NO:5). The second interaction is between a water molecule and the ligand ketone (FIG. 2B). This water molecule and its connected network of hydrogen bonds occupy the same position in the apoenzyme structure. The overall surface topology of the cleft tightly sequesters the (2S)-naringenin molecule (FIG. 2C). The CHI•naringenin complex (SEQ ID NO:9) explains the stereochemical preference of the cyclization reaction; moreover, it suggests why CHIs from different species show moderate selectivity for chalcone and 6′-deoxychalcone as substrates.

Modeling of chalcone, based on the position of (2S)-naringenin, shows that a slight rotation of the trihydroxyl-ring outward in the direction of the active site opening places the 2′-hydroxyl group in position for nucleophilic attack on the α,β-unsaturated double bond of the coumaroyl moiety (FIG. 3A). This rotation preserves the position of the chalcone backbone and the hydrogen bonds between Thr 190 and the water molecule at the backside of the binding site. Formation of (2R)-naringenin would require substantial rearrangements in the active site of CHI due to significant steric clashes between the trihydroxyl-ring and CHI side chains. Although rotation of the trihydroxyl-ring away from the active site entrance could reposition the 2′-hydroxyl group for attack on the opposite face of the α,β-double bond, the side chain of Val 110 sterically prevents this movement from occurring (FIG. 3B). In addition, the opposite side of the substrate double bond could be positioned for attack by the 2′-hydroxyl group in the formation of (2R)-naringenin. This alternative cyclization would be accomplished by rotation of the coumaroyl moiety outward towards the solvent accessible active site entrance. However, Leu 38 and Lys 109 constrain the orientation of the coumaroyl moiety in the binding cleft. Architecturally, the CHI active site limits the substrate's available conformations to ensure stereospecific product formation.

Subtle variations in substrate preference reflected in the K_(m) values for chalcone versus 6′-deoxychalcone exist between CHIs of different species. CHIs from legumes, such as alfalfa, prefer 6′-deoxychalcone as a substrate but the enzymes from non-legumes, like petunia, optimally use chalcone. The structure of the CHI•naringenin complex (SEQ ID NO:9), viewed with reference to the amino acid sequences of different CHIs (SEQ ID NOs:1-8), suggests that Thr 190 and Met 191 may partially modulate substrate preference. In the CHIs from non-legumes, a serine and an isoleucine replace Thr 190 and Met 191, respectively. These two differences may better accommodate the 6′-hydroxyl moiety of chalcone due to a modest increase in active site volume in the vicinity of the trihydroxyl ring.

Catalytic Mechanism

CHI catalyzes an intramolecular reaction utilizing a substrate-derived nucleophile and a carbon-carbon double bond as a Michael acceptor. Two reaction mechanisms have been proposed for (2S)-naringenin formation by CHI. One involves nucleophilic catalysis by an active site residue that forms a covalent intermediate that is released after a SN₂ displacement by the 2′-O⁻ of chalcone. The other mechanism invokes general acid-base catalysis employing an enol intermediate. The structure of CHI clearly supports the latter mechanism.

Examination of the CHI•naringenin complex structure (SEQ ID NO:9) reveals a hydrogen bond network at the bottom of the binding cleft centered about the water molecule that contacts the ketone of (2S)-naringenin (FIGS. 4A and 4B). Of the five amino acids contributing to this network, only Thr 48 and Tyr 106 are conserved in all CHIs (SEQ ID NOs:1-8). The position of the water molecule between (2S)-naringenin and Tyr 106 (SEQ ID NO:9) suggests a reaction mechanism in which the tyrosine activates the water, allowing it to serve as a general acid in the cyclization reaction (FIG. 4C). In the proposed reaction mechanism, the 2′-O⁻ (pK_(a)˜7-8) forms in solution as suggested by studies on the spontaneous cyclization of chalcones. The negatively charged oxygen then attacks the carbon-carbon double bond utilizing a Michael addition with the water molecule at the backside of the active site acting as the general acid in the transient protonation of the intermediate enolate.

To test this reaction mechanism, Tyr 106 (SEQ ID NO:1) was substituted by phenylalanine and the properties of the mutant CHI (SEQ ID NO:13) compared to the wild-type enzyme. The kinetics for the cyclization of 6′-deoxychalcone by wild-type CHI (k_(cat)=4384 min⁻¹; K_(m)=25.7 μM; k_(cat)/K_(m)=1.71×10⁸M⁻¹ min⁻¹) versus those of the reaction catalyzed by the CHI Y106F mutant (k_(cat)=69.0 min⁻¹; K_(m)=29.1 μM; k_(cat)/K_(m)=2.37×10⁶ M⁻¹ min⁻¹) demonstrate that the tyrosine residue contributes to the stabilization of the transition state. The 100-fold reduction in reaction rate is consistent with the decrease in rate associated with the loss of a general acid. However, the observed reaction rate with the mutant remains greater than that of the uncatalyzed cyclization reaction. It is suggested that the structural complementarity of the binding cleft to the transition state of the reaction contributes additional levels of catalytic rate enhancement.

A major contribution to rate enhancement in enzymatic reactions results from bringing substrates or reactive centers in the same molecule together in space. As described above, the topology of the binding cleft limits the flexibility of chalcone and eliminates catalytically unproductive orientations by spatially defining an optimal geometry for (2S)-naringenin formation. This effectively channels the ground state conformation of the substrate into a catalytically productive conformation. Together with contributions from general acid-base catalysis, shape complementarity between the CHI binding pocket and chalcone accelerates the cyclization of chalcone 10⁷-fold over the spontaneous reaction rate.

TABLE 4 Kinetic constants for wild-type and Y106F mutant CHI k_(cat) (min⁻¹) K_(m) (μM) k_(cat)/K_(m) (M⁻¹ min⁻¹) CHI wild-type 4384 ± 517  25.7 ± 5.4 1.71 × 10⁸ (SEQ ID NO: 1) CHI Y106F 69.0 ± 5.1  29.1 ± 3.7 2.37 × 10⁶ (SEQ ID NO: 2)

The three-dimensional structure of CHI, together with the structure of chalcone synthase, provides a useful template for engineering isomerases to develop, diversify and modify flavonoid biosynthetic pathways for crop and food sources, as well as providing novel flavanones for intermediates and leads in drug discovery. All figures were prepared with MOLSCRIPT or GRASP and rendered with POV-Ray.

While the foregoing has been presented with reference to particular embodiments of the invention, it will be appreciated by those skilled in the art that changes in these embodiments may be made without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims.

Table 5. PDB Accession No. 1EYQ (SEQ ID NO:9). The content of Table 5 is hereby incorporated by reference under 37 C.F.R. §1.52(e)(1)(iii) to file “1EYQ.txt” of CD-R disk “Tables”, created Jan. 2, 2007, having file size 342,918 bytes.

Table 6. PDB Accession No. 1FM7 (SEQ ID NO:9). The content of Table 6 is hereby incorporated by reference under 37 C.F.R. §1.52(e)(1)(iii) to file “1FM7.txt” of CD-R disk “Tables”, created Jan. 2, 2007, having file size 325,452 bytes.

Table 7. PDB Accession No. 1FM8 (SEQ ID NO:9). The content of Table 7 is hereby incorporated by reference under 37 C.F.R. §1.52(e)(1)(iii) to file “1FM8.txt” of CD-R disk “Tables”, created Jan. 2, 2007, having file size 315,366 bytes.

Table 8. PDB Accession No. 1JEP (SEQ ID NO:9). The content of Table 8 is hereby incorporated by reference under 37 C.F.R. §1.52(e)(1)(iii) to file “1JEP.txt” of CD-R disk “Tables”, created Jan. 2, 2007, having file size 340,294 bytes. 

1. A method for identifying a compound that binds to chalcone isomerase, said method comprising: a) employing a three-dimensional (3-D) model of chalcone isomerase having the structural coordinates of Table 1, Table 5, Table 6, Table 7 or Table 8, to generate a 3-D model of a chalcone isomerase active site defined by the coordinates of residues 36, 37, 38, 47, 48, 49, 50, 97, 101, 106, 109, 110, 112, 113, 152, 190, 191, and 200 of SEQ ID NO:1, b) designing or selecting a compound that potentially binds to said chalcone isomerase active site, and c) contacting said compound with a chalcone isomerase in vitro and determining its ability to bind thereto, wherein said chalcone isomerase has at least 90% identity with respect to the sequence set forth in SEQ ID NO:1, and has chalcone isomerase enzymatic activity, whereby compounds that bind chalcone isomerase are identified.
 2. The method of claim 1, wherein said chalcone isomerase employed in step (c) is a mutant of a known chalcone isomerase, wherein said mutant has one or more conservative R-group modifications to the amino acids of a wild-type chalcone isomerase.
 3. A method for identifying a compound that inhibits chalcone isomerase enzymatic activity, said method comprising: a) employing a three-dimensional (3-D) model of chalcone isomerase having the structural coordinates of Table 1, Table 5, Table 6, Table 7 or Table 8, to generate a 3-D model of a chalcone isomerase active site defined by the coordinates of residues 36, 37, 38, 47, 48, 49, 50, 97, 101, 106, 109, 110, 112, 113, 150, 152, 190, 191, and 200 of SEQ ID NO:1, b) designing or selecting a compound that potentially binds to said chalcone isomerase active site, and c) contacting said compound with a chalcone isomerase in vitro and determining its ability to inhibit chalcone isomerase enzymatic activity, wherein said chalcone isomerase has at least 90% identity with respect to the sequence set forth in SEQ ID NO:1, and has chalcone isomerase enzymatic activity, whereby compounds that inhibit the activity of chalcone isomerase are identified.
 4. The method of claim 3, wherein said chalcone isomerase employed in step (c) is a mutant of a known chalcone isomerase, wherein said mutant has one or more conservative R-group modifications to the amino acids of a wild-type chalcone isomerase. 